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Pharmacopeial Forum 1260 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

BRIEFING the general principles involved in the manufacture of some of them, particularly on a small scale. Other information that is gi- ven bears on the use of the Pharmacopeial substances in extem- h1151i Pharmaceutical Dosage Forms, USP 32 page poraneous of dosage forms. 663. This general information chapter is being revised in its en- tirety to represent current compendial thinking with respect to official preparations. The proposed revision incorporates con- cepts outlined in a Stimuli to the Revision Process article, Devel- opment of a Compendial Taxonomy and Glossary for Bioavailability, or the extent to which the therapeutic constit- Pharmaceutical Dosage Forms, authored by an Ad Hoc Commit- uent of a pharmaceutical intended for oral or top- tee composed of the chairs of the Pharmaceutical Dosage ical use is available for absorption, is influenced by a variety of Forms Expert Committee, Biopharmaceutics Expert Commit- factors. Among the inherent factors known to affect absorption tee, Nomenclature and Labeling Expert Committee, and the are the method of manufacture or method of compounding; Council of Experts for the revision cycle, 2000—2005, and pub- the size and crystal form or polymorph of the sub- lished in PF 29(5). The Stimuli article proposed a tiered catego- stance; and the diluents and used in formulating the rization for pharmaceutical dosage forms proceeding from dosage form, including fillers, binders, disintegrating agents, to physical form and ultimately release lubricants, coatings, , suspending agents, and dyes. Lu- pattern. This proposed general information chapter emphasizes bricants and coatings are foremost among these. The mainte- the second tier of the compendial taxonomy, the physical dos- nance of a demonstrably high degree of bioavailability requires age form, rather than the route of administration, with the in- particular attention to all aspects of production and quality con- tention of avoiding redundancy for dosage forms given by trol that may affect the nature of the finished dosage form. multiple routes. The proposed revision is organized into four sections provid- ing discussion of general considerations, product quality tests, TERMINOLOGY dosage form monographs, and a glossary. General considera- tions include uniformity, stability, bioavailability, manufac- Occasionally it is necessary to add to the contents of a ture, and route of administration. The discussion of product container just prior to use, usually because of instability of some quality tests reflects the universally applied as well as dosage in the diluted form. Thus, a diluted to yield a suspen- form specific testing that help assure safety and efficacy from sion is called [DRUG] for ; a solid dissolved and dilu- manufacture through shelf life. The dosage form monographs ted to yield a is called [DRUG] for Solution; and a provide general descriptions, discussion of general principles of solution or suspension diluted to yield a more dilute form of their manufacturing or compounding, and recommendations the drug is called [DRUG] Oral Concentrate. After , it is for proper use and storage. The glossary is intended to provide important that the drug be homogeneously dispersed before guidance in selection of official names for official articles but administration. also as a resource to provide definitions beyond those used in official names for dosage forms.Theglossaryclearlydistin- guishes preferred from not preferred terminology. The revised general information chapter presents current concepts relating to the naming of dosage forms. Outdated Pharmaceutical aerosols are products that are packaged un- forms such as , spirits, , and are herein re- der pressure and contain therapeutically active ingredients that cognized as . are defined as typically are released upon activation of an appropriate valve system. for topical use. While inserts are defined as solid dosage forms They are intended for topical application to the as well as for placement within body cavities, are differenti- local application into the nose (nasal aerosols), mouth (lingual ated as only for placement within the . aerosols), or lungs ( aerosols). These products may be This general information chapter is intended to be supple- fitted with valves enabling either continuous or metered-dose mented by more detailed discussion of characteristics, quality delivery; hence, the terms ‘‘[DRUG] Metered Topical Aerosols,’’ tests, and other considerations based on route of administra- ‘‘[DRUG] Metered Nasal Aerosols,’’ etc. tion. Early drafts of such concepts relating to topical and trans- The term ‘‘’’ refers to the fine mist of spray that results dermal dosage forms are presented in PF 35(3) [May–June from most pressurized systems. However, the term has been 2009]. Proposed general test chapter h3i Topical and Transder- broadly misapplied to all self-contained pressurized products, mal Drug Products—Product Quality Tests, providing quality test- some of which deliver foams or semisolid fluids. In the case of ing procedures, complements the performance testing Inhalation Aerosols, the particle size of the delivered proposed in h725i Topical and Drug Products— must be carefully controlled, and the average size of the parti- Product Performance Tests. Additional revision proposals of sim- cles should be under 5 mm. These products are also known as ilar standards for the oral (gastro-intestinal), mucosal, by inha- metered-dose (MDIs). Other aerosol sprays may con- lation, and by routes are planned. tain up to several hundred micrometers in diameter. The basic components of an aerosol system are the container, (BPC: W. Brown.) RTS—C69686 the propellant, the concentrate containing the active ingredi- ent(s), the valve, and the actuator. The nature of these compo- nents determines such characteristics as particle size distribution, uniformity of dose for metered valves, delivery rate, wetness and temperature of the spray, spray pattern and Change to read: velocity or plume geometry, foam density, and fluid .

Types of Aerosols h1151i PHARMACEUTICAL Aerosols consist of two- ( and ) or three-phase (gas, liquid, and solid or liquid) systems. The two-phase aerosol DOSAGE FORMS consists of a solution of active ingredients in liquefied propel- lant and the vaporized propellant. The solvent is composed of the propellant or a of the propellant and cosolvents Dosage forms are provided for most of the Pharmacopeial such as , , and glycols, drug substances, but the processes for the preparation of many which are often used to enhance the of the active in- of them are, in general, beyond the scope of the Pharmacopeia. gredients. In addition to defining the dosage forms, this section presents In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1261

Three-phase systems consist of a suspension or of Containers the active ingredient(s) in addition to the vaporized propel- lants. A suspension consists of the active ingredient(s) that Aerosol containers usually are made of glass, plastic, or metal, may be dispersed in the propellant system with the aid of suit- or a combination of these materials. Glass containers must be able excipients such as wetting agents and/or solid carriers such precisely engineered to provide the maximum in pressure safe- as talc or colloidal silicas. ty and impact resistance. Plastics may be employed to coat A foam aerosol is an emulsion containing one or more active glass containers for improved safety characteristics, or to coat ingredients, , aqueous or nonaqueous , and metal containers to improve corrosion resistance and enhance the propellants. If the propellant is in the internal (discontinu- stability of the . Suitable metals include stainless ous) phase (i.e., of the -in- type), a stable foam is dis- steel, aluminum, and tin-plated steel. Extractables or leachables charged; and if the propellant is in the external (continuous) (e.g., drawing , cleaning agents, etc.) and on phase (i.e., of the water-in-oil type), a spray or a quick-breaking the internal surfaces of containers should be controlled. foam is discharged. Manufacture Propellants Aerosols are usually prepared by one of two general proces- The propellant supplies the necessary pressure within an aer- ses. In the ‘‘cold-fill’’ process, the concentrate (generally cooled osol system to expel material from the container and, in com- to a temperature below 08) and the refrigerated propellant are bination with other components, to convert the material into measured into open containers (usually chilled). The valve-actu- the desired physical form. Propellants may be broadly classified ator assembly is then crimped onto the container to form a as liquefied or compressed having vapor pressures gener- pressure-tight seal. During the interval between propellant ad- ally exceeding atmospheric pressure. Propellants within this dition and crimping, sufficient volatilization of propellant oc- definition include various hydrocarbons, especially halogenat- curs to displace air from the container. In the ‘‘pressure-fill’’ ed derivatives of methane, ethane, and propane, low molecular method, the concentrate is placed in the container, and either weight hydrocarbons such as the butanes and pentanes, and the propellant is forced under pressure through the valve orifice compressed gases such as carbon dioxide, , and ni- after the valve is sealed, or the propellant is allowed to flow un- trous oxide. of propellants are frequently used to ob- der the valve cap and then the valve assembly is sealed (‘‘under- tain desirable pressure, delivery, and spray characteristics. A the-cap’’ filling). In both cases of the ‘‘pressure-fill’’ method, good propellant system should have the proper vapor pressure provision must be made for evacuation of air by means of vac- characteristics consistent with the other aerosol components. uum or displacement with a small amount of propellant vapor. Manufacturing process controls usually include monitoring of proper formulation and propellant fill weight and pressure test- Valves ing, leak testing, and valve function testing of the finished aer- osol. Microbiological attributes should also be controlled. The primary function of the valve is to regulate the flow of the therapeutic agent and propellant from the container. The spray characteristics of the aerosol are influenced by orifice dimen- Extractable Substances sion, number, and location. Most aerosol valves provide for continuous spray operation and are used on most topical prod- Since pressurized inhalers and aerosols are normally formulat- ucts. However, pharmaceutical products for oral or nasal inha- ed with organic solvents as the propellant or the vehicle, leach- lation often utilize metered-dose valves that must deliver a ing of extractables from the elastomeric and plastic uniform quantity of spray upon each valve activation. The accu- components into the formulation is a potentially serious prob- racy and reproducibility of the doses delivered from metering lem. Thus, the composition and the quality of materials used in valves are generally good, comparing favorably to the uniformi- the manufacture of the valve components (e.g., stem, gaskets, ty of solid dosage forms such as tablets and capsules. However, housing, etc.) must be carefully selected and controlled. Their when aerosol packages are stored improperly, or when they compatibility with formulation components should be well es- have not been used for long periods of time, valves must be tablished so as to prevent distortion of the valve components primed before use. Materials used for the manufacture of valves and to minimize changes in the medication delivery, leak rate, should be inert to the used. Plastic, rubber, alumi- and impurity profile of the drug product over time. The extract- num, and stainless steel valve components are commonly used. able profiles of a representative sample of each of the elasto- Metered-dose valves must deliver an accurate dose within spec- meric and plastic components of the valve should be ified tolerances. established under specified conditions and should be correlated to the extractable profile of the aged drug product or placebo, to ensure reproducible quality and purity of the drug product. Actuators Extractables, which may include polynuclear aromatics, nitrosa- mines, vulcanization accelerators, antioxidants, plasticizers, An actuator is the fitting attached to an aerosol valve stem, monomers, etc., should be identified and minimized wherever which when depressed or moved, opens the valve, and directs possible. the spray containing the drug preparation to the desired area. Specifications and limits for individual and total extractables The actuator usually indicates the direction in which the prep- from different valve components may require the use of differ- aration is dispensed and protects the hand or finger from the ent analytical methods. In addition, the standard USP biological refrigerant effects of the propellant. Actuators incorporate an testing (see the general test chapters Biological Reactivity Tests, orifice that may vary widely in size and shape. The size of this In Vitro h87i and Biological Reactivity Tests, In Vivo h88i) as well as orifice, the expansion chamber design, and the nature of the other safety data may be needed. propellant and formulation influence the delivered dose as well as the physical characteristics of the spray, foam, or stream of solid particles dispensed. For inhalation aerosols, an actuator Labeling capable of delivering the medication in the proper particle size Revision In-Process range and with the appropriate spray pattern and plume geom- Medicinal aerosols should contain at least the following etry is utilized. warning information on the label as in accordance with appro- priate regulations. Warning—Avoid inhaling. Avoid spraying into eyes or onto other mucous membranes.

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1262 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

NOTE—The statement ‘‘Avoid inhaling’’ is not necessary for tins having relatively high strength. Either type may be preparations specifically designed for use by inhalation. The used, but blends of pork skin and bone are often used phrase ‘‘or other mucous membranes’’ is not necessary for pre- to optimize shell clarity and toughness. Hard-shell capsules also parations specifically designed for use on mucous membranes. may be formed from or other suitable substances. Hard- Warning—Contents under pressure. Do not puncture or in- shell capsules may also contain colorants, such as D&C and cinerate container. Do not expose to heat or store at tempera- FD&C dyes or the various iron oxides, opaquing agents such tures above 1208 F (498 C). Keep out of reach of children. as titanium dioxide, dispersing agents, hardening agents such In addition to the aforementioned warnings, the label of a as , and . They normally contain between drug packaged in an aerosol container in which the propellant 10% and 15% water. consists in whole or in part of a halocarbon or hydrocarbon Hard gelatin capsules are made by a process that involves shall, where required under regulations of the FDA, bear either dipping shaped pins into gelatin solutions, after which the gel- of the following warnings: atin films are dried, trimmed, and removed from the pins, and Warning—Do not inhale directly; deliberate inhalation of the body and cap pieces are joined. Starch capsules are made contents can cause death. by injection molding a mixture of starch and water, after which the capsules are dried. A separate mold is used for caps and bo- Warning—Use only as directed; intentional misuse by deliber- dies, and the two parts are supplied separately. The empty cap- ately concentrating and inhaling the contents can be harmful sules should be stored in tight containers until they are filled. or fatal. Since gelatin is of animal origin and starch is of vegetable origin, capsules made with these materials should be protected from potential sources of microbial contamination. BOLUSES Hard-shell capsules typically are filled with , beads, or granules. Inert beads (nonpareils) may be coated with ac- Boluses are large elongated tablets intended for administra- tive ingredients and coating compositions that provide extend- tion to animals (see Tablets). ed-release profiles or enteric properties. Alternatively, larger- dose active ingredients themselves may be suitably formed into pellets and then coated. Semisolids or liquids also may be filled CAPSULES into hard-shell capsules; however, when the latter are encapsu- lated, one of the sealing techniques must be employed to pre- Capsules are solid dosage forms in which the drug is enclosed vent leakage. within either a hard or soft soluble container or ‘‘shell.’’ The In hard gelatin filling operations, the body and cap of shells are usually formed from gelatin; however, they also may the shell are separated prior to dosing. In hard starch shell filling be made from starch or other suitable substances. Hard-shell operations, the bodies and caps are supplied separately and are capsule sizes range from No. 5, the smallest, to No. 000, which fed into separate hoppers of the filling machine. Machines em- is the largest, except for veterinary sizes. However, size No. ploying various dosing principles may be employed to fill pow- 00 generally is the largest size acceptable to patients. Size 0 ders into hard-shell capsules; however, most fully automatic hard gelatin capsules having an elongated body (known as size machines form powder plugs by compression and eject them OE) also are available, which provide greater fill capacity with- into empty capsule bodies. Accessories to these machines gen- outanincreaseindiameter.Hardgelatincapsulesconsistof erally are available for the other types of fills. Powder formula- two, telescoping cap and body pieces. Generally, there are tions often require adding fillers, lubricants, and glidants to the unique grooves or indentations molded into the cap and body active ingredients to facilitate encapsulation. The formulation, portions to provide a positive closure when fully engaged, as well as the method of filling, particularly the degree of com- which helps prevent the accidental separation of the filled cap- paction, may influence the rate of drug release. The addition of sules during shipping and handling. Positive closure also may wetting agents to the powder mass is common where the ac- be affected by spot fusion (‘‘welding’’) of the cap and body tive ingredient is hydrophobic. Disintegrants also may be in- pieces together through direct thermal means or by application cluded in powder formulations to facilitate deaggregation of ultrasonic energy. Factory-filled hard gelatin capsules may be and dispersal of capsule plugs in the gut. Powder formulations completely sealed by banding, a process in which one or more often may be produced by dry blending; however, bulky formu- layers of gelatin are applied over the seam of the cap and body, lations may require densification by roll compaction or other or by a liquid fusion process wherein the filled capsules are wet- suitable granulation techniques. ted with a hydroalcoholic solution that penetrates into the Powder mixtures that tend to liquefy may be dispensed in space where the cap overlaps the body, and then dried. hard-shell capsules if an absorbent such as carbo- Hard-shell capsules made from starch consist of two, fitted nate, colloidal dioxide, or other suitable substance is cap and body pieces. Since the two pieces do not telescope used. Potent drugs are often mixed with an inert diluent before or interlock positively, they are sealed together at the time of being filled into capsules. Where two mutually incompatible filling to prevent their separation. Starch capsules are sealed drugs are prescribed together, it is sometimes possible to place by the application of a hydroalcoholic solution to the recessed one in a small capsule and then enclose it with the second drug section of the cap immediately prior to its being placed onto in a larger capsule. Incompatible drugs also can be separated by the body. placing coated pellets or tablets, or soft-shell capsules of one The banding of hard-shell gelatin capsules or the liquid seal- drug into the capsule shell before adding the second drug. ing of hard-shell starch capsules enhances consumer safety by Thixotropic semisolids may be formed by gelling liquid drugs making the capsules difficult to open without causing visible, or vehicles with colloidal silicas or powdered high molecular obvious damage, and may improve the stability of contents weight polyethylene glycols. Various waxy or fatty compounds by limiting O2 penetration. Industrially filled hard-shell capsules may be used to prepare semisolid matrices by fusion. also are often of distinctive color and shape or are otherwise Soft-shell capsules made from gelatin (sometimes called soft- marked to identify them with the manufacturer. Additionally, ) or other suitable material require large-scale production such capsules may be printed axially or radially with strengths, methods. The soft gelatin shell is somewhat thicker than that product codes, etc. Pharmaceutical-grade inks are us- of hard-shell capsules and may be plasticized by the addition ually based on and employ FDA-approved pigments and of a polyol such as or glycerin. The ratio of dry plastici- lake dyes. zer to dry gelatin determines the ‘‘hardness’’ of the shell and In extemporaneous prescription practice, hard-shell capsules may be varied to accommodate environmental conditions as may be hand-filled; this permits the prescriber a latitude of well as the nature of the contents. Like hard shells, the shell choice in selecting either a single drug or a combination of composition may include approved dyes and pigments, opa- drugs at the exact dosage level considered best for the individ- quing agents such as titanium dioxide, and preservatives. Fla- ual patient. This flexibility gives hard-shell capsules an advan- vors may be added and up to 5% sucrose may be included tage over compressed tablets and soft-shell capsules as a for its sweetness and to produce a chewable shell. Soft gelatin dosage form. Hard-shell capsules are usually formed from gela- shells normally contain 6% to 13% water. Soft-shell capsules In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1263 also may be printed with a product code, strength, etc. In most cases, soft-shell capsules are filled with liquid contents. Typical- ly, active ingredients are dissolved or suspended in a liquid ve- Creams are semisolid dosage forms containing one or more hicle. Classically, an oleaginous vehicle such as a vegetable oil drug substances dissolved or dispersed in a suitable base. This was used; however, nonaqueous, water-miscible liquid vehicles term has traditionally been applied to semisolids that possess a such as the lower-molecular-weight polyethylene glycols are relatively fluid consistency formulated as either water-in-oil more common today due to fewer bioavailability problems. (e.g., Cold ) or oil-in-water (e.g., Fluocinolone Acetonide Available in a wide variety of sizes and shapes, soft-shell cap- Cream) emulsions. However, more recently the term has been sules are both formed, filled, and sealed in the same machine; restricted to products consisting of oil-in-water emulsions or typically, this is a rotary die process, although a plate process or aqueous microcrystalline dispersions of long-chain fatty acids reciprocating die process also may be employed. Soft-shell cap- or alcohols that are water washable and more cosmetically sules also may be manufactured in a bubble process that forms and aesthetically acceptable. Creams can be used for adminis- seamless spherical capsules. With suitable equipment, tering drugs via the vaginal route (e.g., Triple Sulfa Vaginal and other dry also may be filled into soft-shell capsules. Cream). Liquid-filled capsules of either type involve similar formula- tion technology and offer similar advantages and limitations. For instance, both may offer advantages over dry-filled capsules ELIXIRS and tablets in content uniformity and drug dissolution. Greater homogeneity is possible in liquid systems, and liquids can be See Solutions. metered more accurately. Drug dissolution may benefit be- cause the drug may already be in solution or at least suspended in a hydrophilic vehicle. However, the contact between the EMULSIONS hard or soft shell and its liquid content is more intimate than exists with dry-filled capsules, and this may enhance the chanc- Emulsions are two-phase systems in which one liquid is dis- es for undesired interactions. The liquid nature of capsule con- persed throughout another liquid in the form of small droplets. tents presents different technological problems than dry-filled Where oil is the dispersed phase and an is the capsules in regard to disintegration and dissolution testing. continuous phase, the system is designated as an oil-in-water From formulation, technological, and biopharmaceutical emulsion. Conversely, where water or an aqueous solution is points of view, liquid-filled capsules of either type have more the dispersed phase and oil or oleaginous material is the contin- in common than liquid-filled and dry-filled capsules having uous phase, the system is designated as a water-in-oil emulsion. the same shell composition. Thus, for compendial purposes, Emulsions are stabilized by emulsifying agents that prevent co- standards and methods should be established based on capsule alescence, the merging of small droplets into larger droplets contents rather than on whether the contents are filled into and, ultimately, into a single separated phase. Emulsifying hard- or soft-shell capsules. agents (surfactants) do this by concentrating in the interface between the droplet and external phase and by providing a physical barrier around the particle to coalescence. Surfactants DELAYED-RELEASE CAPSULES also reduce the interfacial tension between the phases, thus in- creasing the ease of emulsification upon mixing. Capsules may be coated, or, more commonly, encapsulated Natural, semisynthetic, and synthetic hydrophilic granules may be coated to resist releasing the drug in the gas- may be used in conjunction with surfactants in oil-in-water tric fluid of the where a delay is important to alleviate emulsions as they accumulate at interfaces and also increase potential problems of drug inactivation or gastric mucosal irri- the viscosity of the aqueous phase, thereby decreasing the rate tation. The term ‘‘delayed-release’’ is used for Pharmacopeial of formation of aggregates of droplets. Aggregation is generally monographs on enteric coated capsules that are intended to accompanied by a relatively rapid separation of an emulsion in- delay the release of medicament until the capsule has passed to a droplet-rich and droplet-poor phase. Normally the density through the stomach, and the individual monographs include of an oil is lower than that of water, in which case the oil - tests and specifications for Drug release (see Drug Release h724i) lets and droplet aggregates rise, a process referred to as cream- or Disintegration (see Disintegration h701i). ing. The greater the rate of aggregation, the greater the droplet size and the greater the rate of creaming. The water droplets in a water-in-oil emulsion generally because of their EXTENDED-RELEASE CAPSULES greater density. The consistency of emulsions varies widely, ranging from eas- Extended-release capsules are formulated in such manner as ily pourable liquids to semisolid creams. Generally oil-in-water to make the contained medicament available over an extended creams are prepared at high temperature, where they are fluid, period of time following . Expressions such as ‘‘pro- and cooled to room temperature, whereupon they solidify as a longed-action,’’ ‘‘repeat-action,’’ and ‘‘sustained-release’’ have result of solidification of the internal phase. When this is the also been used to describe such dosage forms. However, the case, a high internal-phase volume to external-phase volume term ‘‘extended-release’’ is used for Pharmacopeial purposes ratio is not necessary for semisolid character, and, for example, and requirements for Drug release (see Drug Release h724i) typ- stearic acid creams or vanishing creams are semisolid with as ically are specified in the individual monographs. little as 15% internal phase. Any semisolid character with wa- ter-in-oil emulsions generally is attributable to a semisolid exter- nal phase. CONCENTRATE FOR DIP All emulsions require an agent because the aqueous phase is favorable to the growth of . Concentrate for Dip is a preparation containing one or more The presence of a is particularly critical in oil-in-wa- active ingredients usually in the form of a or solution. It is ter emulsions where contamination of the external phase oc- used to prepare a diluted suspension, emulsion, or solution of curs readily. Since fungi and yeasts are found with greater the active ingredient(s) for the prevention and treatment of ec- frequency than bacteria, fungistatic as well as bacteriostatic toparasitic infestations of animals. The diluted preparation properties are desirable. Bacteria have been shown to degrade Revision In-Process (Dip) is applied by complete immersion of the animal or, where nonionic and anionic emulsifying agents, glycerin, and many appropriate, by spraying. Concentrate for Dip may contain suit- natural stabilizers such as tragacanth and . able antimicrobial preservatives. Complications arise in preserving emulsion systems, as a re- sult of partitioning of the antimicrobial agent out of the aque- ous phase where it is most needed, or of complexation with emulsion ingredients that reduce effectiveness. Therefore, the effectiveness of the preservative system should always be tested

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1264 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

in the final product. Preservatives commonly used in emulsions include methyl-, ethyl-, propyl-, and butyl-, , and quaternary ammonium compounds. Inhalations are drugs or solutions or suspensions of one or See also Creams and Ointments. more drug substances administered by the nasal or oral respi- ratory route for local or systemic effect. Solutions of drug substances in sterile water for inhalation or EXTRACTS AND FLUIDEXTRACTS in sodium chloride inhalation solution may be nebulized by use of inert gases. are suitable for the administration of Extracts are concentrated preparations of vegetable or ani- inhalation solutions only if they give droplets sufficiently fine mal drugs obtained by removal of the active constituents of and uniform in size so that the mist reaches the bronchioles. the respective drugs with suitable menstrua, by evaporation Nebulized solutions may be breathed directly from the nebuliz- of all or nearly all of the solvent, and by adjustment of the re- er or the may be attached to a plastic face mask, tent, sidual masses or powders to the prescribed standards. or intermittent positive pressure breathing (IPPB) machine. In the manufacture of most extracts, the drugs are extracted Another group of products, also known as metered-dose in- by percolation. The entire percolates are concentrated, gener- halers (MDIs) are propellant-driven drug suspensions or solu- ally by distillation under reduced pressure in order to subject tions in liquified gas propellant with or without a cosolvent the drug principles to as little heat as possible. and are intended for delivering metered doses of the drug to Fluidextracts are liquid preparations of vegetable drugs, con- the . An MDI contains multiple doses, often ex- taining alcohol as a solvent or as a preservative, or both, and so ceeding several hundred. The most common single-dose vol- made that, unless otherwise specified in an individual mono- umes delivered are from 25 to 100 mL (also expressed as mg) graph, each mL contains the therapeutic constituents of 1 g per actuation. of the standard drug that it represents. Examples of MDIs containing drug solutions and suspensions A fluidextract that tends to deposit sediment may be aged in this pharmacopeia are Inhalation Aerosol and Iso- and filtered or the clear portion decanted, provided the result- proterenol Hydrochloride and Bitartrate Inhalation ing clear liquid conforms to the Pharmacopeial standards. Aerosol, respectively. Fluidextracts may be prepared from suitable extracts. Powders may also be administered by mechanical devices that require manually produced pressure or a deep inhalation by the patient (e.g., Cromolyn Sodium for Inhalation). GELS A special class of inhalations termed consists of drugs or combination of drugs, that by virtue of their high va- Gels (sometimes called Jellies) are semisolid systems consist- por pressure, can be carried by an air current into the nasal pas- ing of either suspensions made up of small inorganic particles or sage where they exert their effect. The container from which large organic molecules interpenetrated by a liquid. Where the the generally is administered is known as an . gel mass consists of a network of small discrete particles, the gel is classified as a two-phase system (e.g., Aluminum Hydroxide Gel). In a two-phase system, if the particle size of the dispersed INJECTIONS phase is relatively large, the gel mass is sometimes referred to as a magma (e.g., Bentonite Magma). Both gels and magmas may An Injection is a preparation intended for parenteral admin- be thixotropic, forming semisolids on standing and becoming istration or for constituting or diluting a parenteral article prior liquid on agitation. They should be shaken before use to ensure to administration (see Injections h1i). homogeneity and should be labeled to that effect. (See Suspen- Each container of an Injection is filled with a volume in slight sions.) excess of the labeled ‘‘size’’ or that volume that is to be with- Single-phase gels consist of organic macromolecules uni- drawn. The excess volumes recommended in the accompany- formly distributed throughout a liquid in such a manner that ing table are usually sufficient to permit withdrawal and no apparent boundaries exist between the dispersed macro- administration of the labeled volumes. molecules and the liquid. Single-phase gels may be made from synthetic macromolecules (e.g., Carbomer) or from natural gums (e.g., Tragacanth). The latter preparations are also called Recommended Excess Volume mucilages. Although these gels are commonly aqueous, alco- For Mobile For Viscous hols and oils may be used as the continuous phase. For exam- Labeled Size Liquids Liquids ple, can be combined with a polyethylene resin to form an oleaginous ointment base. 0.5 mL 0.10 mL 0.12 mL Gels can be used to administer drugs topically or into body 1.0 mL 0.10 mL 0.15 mL cavities (e.g., Phenylephrine Hydrochloride Nasal Jelly). 2.0 mL 0.15 mL 0.25 mL 5.0 mL 0.30 mL 0.50 mL 10.0 mL 0.50 mL 0.70 mL 20.0 mL 0.60 mL 0.90 mL IMPLANTS (PELLETS) 30.0 mL 0.80 mL 1.20 mL 50.0 mL or more 2% 3% Implants or pellets are small sterile solid masses consisting of a highly purified drug (with or without excipients) made by compression or molding. They are intended for implantation in the body (usually subcutaneously) for the purpose of provid- ing continuous release of the drug over long periods of time. IRRIGATIONS Implants are administered by means of a suitable special injec- tor or surgical incision. This dosage form has been used to ad- Irrigations are sterile solutions intended to bathe or flush o- minister hormones such as or . They are pen wounds or body cavities. They are used topically, never par- packaged individually in sterile or foil strips. enterally. They are labeled to indicate that they are not intended for injection. INFUSIONS, INTRAMAMMARY LOTIONS Intramammary infusions are suspensions of drugs in suitable oil vehicles. These preparations are intended for veterinary use See Solutions or Suspensions. only, and are administered by instillation via the teat canals into the udders of -producing animals. In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1265

LOZENGES cases, it is necessary to use a base that is less than ideal in order to achieve the stability required. Drugs that hydrolyze rapidly, Lozenges are solid preparations, that are intended to dissolve for example, are more stable in hydrocarbon bases than in ba- or disintegrate slowly in the mouth. They contain one or more ses containing water, even though they may be more effective medicaments, usually in a flavored, sweetened base. They can in the latter. be prepared by molding (gelatin and/or fused sucrose or sorbi- tol base) or by compression of sugar-based tablets. Molded loz- enges are sometimes referred to as while compressed OPHTHALMIC PREPARATIONS lozenges are often referred to as troches. They are usually in- tended for treatment of local irritation or of the Drugs are administered to the eyes in a wide variety of dos- mouth or throat but may contain active ingredients intended age forms, some of which require special consideration. They for systemic absorption after swallowing. are discussed in the following paragraphs.

OINTMENTS Ointments Ointments are semisolid preparations intended for external Ophthalmic ointments are ointments for application to the application to the skin or mucous membranes. eye. Special precautions must be taken in the preparation of Ointment bases recognized for use as vehicles fall into four ophthalmic ointments. They are manufactured from sterilized general classes: the hydrocarbon bases, the absorption bases, ingredients under rigidly aseptic conditions and meet the re- the water-removable bases, and the water-soluble bases. Each quirements under Sterility Tests h71i. If the specific ingredients therapeutic ointment possesses as its base a representative of used in the formulation do not lend themselves to routine ster- one of these four general classes. ilization techniques, ingredients that meet the sterility require- ments described under Sterility Tests h71i, along with aseptic manufacture, may be employed. Ophthalmic ointments must Hydrocarbon Bases contain a suitable substance or mixture of substances to pre- vent growth of, or to destroy, microorganisms accidentally in- These bases, which are known also as ‘‘oleaginous ointment troduced when the container is opened during use, unless bases,’’ are represented by Petrolatum and White Oint- otherwise directed in the individual monograph, or unless the ment. Only small amounts of an aqueous component can be formula itself is bacteriostatic (see Added Substances under Oph- incorporated into them. They serve to keep medicaments in thalmic Ointments h771i). The medicinal agent is added to the prolonged contact with the skin and act as occlusive dressings. ointment base either as a solution or as a micronized powder. Hydrocarbon bases are used chiefly for their emollient effects, The finished ointment must be free from large particles and and are difficult to wash off. They do not ‘‘dry out’’ or change must meet the requirements for Leakage and for Metal Particles noticeably on aging. under Ophthalmic Ointments h771i. The immediate containers for ophthalmic ointments shall be sterile at the time of filling and closing. It is mandatory that the immediate containers Absorption Bases for ophthalmic ointments be sealed and tamper-proof so that sterility is assured at time of first use. This class of bases may be divided into two groups: the first The ointment base that is selected must be nonirritating to group consisting of bases that permit the incorporation of the eye, permit diffusion of the drug throughout the secretions aqueous solutions with the formation of a water-in-oil emulsion bathing the eye, and retain the activity of the medicament for a (Hydrophilic Petrolatum and Lanolin), and the second group con- reasonable period under proper storage conditions. sisting of water-in-oil emulsions that permit the incorporation Petrolatum is mainly used as a base for ophthalmic drugs. of additional quantities of aqueous solutions (Lanolin). Absorp- Some absorption bases, water-removable bases, and water-- tion bases are useful also as emollients. uble bases may be desirable for water-soluble drugs. Such bases allow for better of water-soluble medicaments, but they must be nonirritating to the eye. Water-Removable Bases Such bases are oil-in-water emulsions, e.g., Hydrophilic Oint- Solutions ment, and are more correctly called ‘‘creams.’’ (See Creams.) They are also described as ‘‘water-washable,’’ since they may Ophthalmic solutions are sterile solutions, essentially free be readily washed from the skin or clothing with water, an at- from foreign particles, suitably compounded and packaged tribute that makes them more acceptable for cosmetic reasons. for instillation into the eye. Preparation of an ophthalmic solu- Some medicaments may be more effective in these bases than tion requires careful consideration of such factors as the inher- in hydrocarbon bases. Other advantages of the water-remov- ent toxicity of the drug itself, isotonicity value, the need for able bases are that they may be diluted with water and that buffering agents, the need for a preservative (and, if needed, they favor the absorption of serous discharges in dermatologi- its selection), sterilization, and proper packaging. Similar con- cal conditions. siderations are also made for nasal and otic products.

Water-Soluble Bases ISOTONICITY VALUE This group of so-called ‘‘greaseless ointment bases’’ compris- Lacrimal fluid is isotonic with , having an isotonicity val- es water-soluble constituents. Ointment is ue corresponding to that of a 0.9% sodium chloride solution. the only Pharmacopeial preparation in this group. Bases of this Ideally, an ophthalmic solution should have this isotonicity val- type offer many of the advantages of the water-removable ba- ue; but the eye can tolerate isotonicity values as low as that of a ses and, in addition, contain no water-insoluble substances 0.6% sodium chloride solution and as high as that of a 2.0% Revision In-Process such as petrolatum, anhydrous lanolin, or . They are more sodium chloride solution without marked discomfort. correctly called ‘‘Gels.’’ (See Gels.) Some ophthalmic solutions are necessarily hypertonic in or- Choice of Base—The choice of an ointment base depends der to enhance absorption and provide a of the upon many factors, such as the action desired, the nature of the active ingredient(s) strong enough to exert a prompt and effec- medicament to be incorporated and its bioavailability and sta- tive action. Where the amount of such solutions used is small, bility, and the requisite shelf-life of the finished product. In some dilution with lacrimal fluid takes place rapidly so that discomfort from the hypertonicity is only temporary. However, any adjust-

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1266 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

ment toward isotonicity by dilution with tears is negligible PRESERVATION where large volumes of hypertonic solutions are used as collyria to wash the eyes; it is, therefore, important that solutions used Ophthalmic solutions may be packaged in multiple-dose for this purpose be approximately isotonic. containers when intended for the individual use of one patient and where the ocular surfaces are intact. It is mandatory that the immediate containers for ophthalmic solutions be sealed BUFFERING and tamper-proof so that sterility is assured at time of first use. Each solution must contain a suitable substance or mixture Many drugs, notably alkaloidal salts, are most effective at pH of substances to prevent the growth of, or to destroy, microor- levels that favor the undissociated free bases. At such pH levels, ganisms accidentally introduced when the container is opened however, the drug may be unstable so that compromise levels during use. must be found and held by means of buffers. One purpose of Where intended for use in surgical procedures, ophthalmic buffering some ophthalmic solutions is to prevent an increase in solutions, although they must be sterile, should not contain an- pH caused by the slow release of hydroxyl ions by glass. Such a tibacterial agents, since they may be irritating to the ocular tis- rise in pH can affect both the solubility and the stability of the sues. drug. The decision whether or not buffering agents should be added in preparing an ophthalmic solution must be based on several considerations. Normal tears have a pH of about 7.4 and possess some buffer capacity. The application of a solution to the eye stimulates the flow of tears and the rapid neutralization A pharmaceutical grade of methylcellulose (e.g., 1% if the of any excess hydrogen or hydroxyl ions within the buffer capa- viscosity is 25 centipoises, or 0.25% if 4000 centipoises) or oth- city of the tears. Many ophthalmic drugs, such as alkaloidal er suitable thickening agents such as hydroxypropyl methylcel- salts, are weakly acidic and have only weak buffer capacity. lulose or polyvinyl alcohol occasionally are added to Where only 1 or 2 drops of a solution containing them are add- ophthalmic solutions to increase the viscosity and prolong con- ed to the eye, the buffering action of the tears is usually ade- tact of the drug with the tissue. The thickened ophthalmic so- quate to raise the pH and prevent marked discomfort. In lution must be free from visible particles. some cases pH may vary between 3.5 and 8.5. Some drugs, no- tably pilocarpine hydrochloride and epinephrine bitartrate, are more acid and overtax the buffer capacity of the lacrimal fluid. Suspensions Ideally, an ophthalmic solution should have the same pH, as well as the same isotonicity value, as lacrimal fluid. This is not Ophthalmic suspensions are sterile liquid preparations con- usually possible since, at pH 7.4, many drugs are not apprecia- taining solid particles dispersed in a liquid vehicle intended bly soluble in water. Most alkaloidal salts precipitate as the free for application to the eye (see Suspensions). It is imperative that alkaloid at this pH. Additionally, many drugs are chemically un- such suspensions contain the drug in a micronized form to pre- stable at pH levels approaching 7.4. This instability is more vent irritation and/or scratching of the cornea. Ophthalmic sus- marked at the high temperatures employed in heat sterilization. pensions should never be dispensed if there is evidence of For this reason, the buffer system should be selected that is caking or aggregation. nearest to the physiological pH of 7.4 and does not cause pre- cipitation of the drug or its rapid deterioration. An ophthalmic preparation with a buffer system approaching Strips the physiological pH can be obtained by mixing a sterile solu- tion of the drug with a sterile using aseptic tech- Fluorescein sodium solution should be dispensed in a sterile, nique. Even so, the possibility of a shorter shelf-life at the higher single-use container or in the form of a sterile, impregnated pa- pH must be taken into consideration, and attention must be di- per strip. The strip releases a sufficient amount of the drug for rected toward the attainment and maintenance of sterility diagnostic purposes when touched to the eye being examined throughout the manipulations. for a foreign body or a corneal abrasion. Contact of the paper Many drugs, when buffered to a therapeutically acceptable with the eye may be avoided by leaching the drug from the pH, would not be stable in solution for long periods of time. strip onto the eye with the aid of sterile water or sterile sodium These products are lyophilized and are intended for reconstitu- chloride solution. tion immediately before use (e.g., Acetylcholine Chloride for Oph- thalmic Solution). PASTES

STERILIZATION Pastes are semisolid dosage forms that contain one or more drug substances intended for topical application. One class is The sterility of solutions applied to an injured eye is of the made from a single-phase aqueous gel (e.g., Carboxymethylce- greatest importance. Sterile preparations in special containers llulose Sodium Paste). The other class, the fatty pastes (e.g., for individual use on one patient should be available in every Oxide Paste), consists of thick, stiff ointments that do not ordi- hospital, office, or other installation where accidentally or sur- narily flow at body temperature, and therefore serve as protec- gically traumatized eyes are treated. The method of attaining tive coatings over the areas to which they are applied. sterility is determined primarily by the character of the particu- The fatty pastes appear less greasy and more absorptive than lar product (see Sterilization and Sterility Assurance of Compen- ointments by reason of a high proportion of drug substance(s) dial Articles h1211i). having an affinity for water. These pastes tend to absorb serous Whenever possible, sterile membrane filtration under aseptic secretions, and are less penetrating and less macerating than conditions is the preferred method. If it can be shown that pro- ointments, so that they are preferred for acute lesions that have duct stability is not adversely affected, sterilization by autoclav- a tendency towards crusting, vesiculation, or oozing. ing in the final container is also a preferred method. A dental paste is intended for adhesion to the mucous Buffering certain drugs near the physiological pH range membrane for local effect (e.g., Dental makes them quite unstable at high temperature. Paste). Some paste preparations intended for administration to Avoiding the use of heat by employing a bacteria-retaining animals are applied orally. The paste is squeezed into the mouth filter is a valuable technique, provided caution is exercised in of the animal, generally at the back of the tongue, or is spread the selection, assembly, and use of the equipment. Single-filtra- inside the mouth. tion, presterilized disposable units are available and should be utilized wherever possible. In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1267

PELLETS id dosage forms. For all solutions, but particularly those containing volatile solvents, tight containers, stored away from See Implants. excessive heat, should be used. Consideration should also be given to the use of light-resistant containers when photolytic chemical degradation is a potential stability problem. Dosage POWDERS forms categorized as ‘‘Solutions’’ are classified according to route of administration, such as ‘‘Oral Solutions’’ and ‘‘Topical Powders are intimate mixtures of dry, finely divided drugs Solutions,’’ or by their solute and solvent systems, such as ‘‘Spir- and/or chemicals that may be intended for internal (Oral Pow- its,’’ ‘‘Tinctures,’’ and ‘‘.’’ Solutions intended for paren- ders) or external (Topical Powders) use. Because of their greater teral administration are officially entitled ‘‘Injections’’ (see specific surface area, powders disperse and dissolve more read- Injections h1i). ily than compacted dosage forms. Children and those adults who experience difficulty in swallowing tablets or capsules may find powders more acceptable. Drugs that are too bulky Oral Solutions to be formed into tablets or capsules of convenient size may be administered as powders. Immediately prior to use, oral Oral Solutions are liquid preparations, intended for oral ad- powders are mixed in a beverage or apple . ministration, that contain one or more substances with or with- Often, stability problems encountered in liquid dosage forms out flavoring, sweetening, or coloring agents dissolved in water are avoided in powdered dosage forms. Drugs that are unstable or cosolvent-water mixtures. Oral Solutions may be formulated in aqueous suspensions or solutions may be prepared in the for direct to the patient or they may be dis- form of granules or powders. These are intended to be consti- pensed in a more concentrated form that must be diluted prior tuted by the pharmacist by the addition of a specified quantity to administration. It is important to recognize that dilution with of water just prior to dispensing. Because these constituted water of Oral Solutions containing cosolvents, such as alcohol, products have limited stability, they are required to have a spec- could lead to precipitation of some ingredients. Hence, great ified expiration date after constitution and may require storage care must be taken in diluting concentrated solutions when co- in a refrigerator. solvents are present. Preparations dispensed as soluble solids or Oral powders may be dispensed in doses premeasured by the soluble mixtures of solids, with the intent of dissolving them in a pharmacist, i.e., divided powders, or in bulk. Traditionally, di- solvent and administering them orally, are designated ‘‘for Oral vided powders have been wrapped in materials such as bond Solution’’ (e.g., Potassium Chloride for Oral Solution). paper and parchment. However, the pharmacist may provide Oral Solutions containing high of sucrose or greater protection from the environment by sealing individual other traditionally have been designated as Syrups. A doses in small cellophane or polyethylene envelopes. near-saturated solution of sucrose in purified water, for exam- Granules for veterinary use may be administered by sprin- ple, is known as or ‘‘Simple Syrup.’’ Through common kling the dry powder on animal feed or by mixing it with animal usage the term, syrup, also has been used to include any other . liquid dosage form prepared in a sweet and viscid vehicle, in- Bulk oral powders are limited to relatively nonpotent drugs cluding oral suspensions. such as laxatives, antacids, dietary supplements, and certain an- In addition to sucrose and other sugars, certain polyols such algesics that the patient may safely measure by the teaspoonful as sorbitol or glycerin may be present in Oral Solutions to inhibit or capful. Other bulky powders include powders, tooth and to modify solubility, , mouth-feel, and powders, and dusting powders. Bulk powders are best dis- other vehicle properties. Antimicrobial agents to prevent the pensed in tight, wide-mouth glass containers to afford maxi- growth of bacteria, yeasts, and molds are generally also pre- mum protection from the atmosphere and to prevent the loss sent. Some sugarless Oral Solutions contain sweetening agents of volatile constituents. such as sorbitol or , as well as thickening agents such Dusting powders are impalpable powders intended for topi- as the gums. Such viscid sweetened solutions, contain- cal application. They may be dispensed in sifter-top containers ing no sugars, are occasionally prepared as vehicles for admin- to facilitate dusting onto the skin. In general, dusting powders istration of drugs to diabetic patients. should be passed through at least a 100-mesh sieve to assure Many oral solutions, that contain alcohol as a cosolvent, have freedom from grit that could irritate traumatized areas (see been traditionally designated as Elixirs. However, many others Powder Fineness h811i). designated as Oral Solutions also contain significant amounts of alcohol. Since high concentrations of alcohol can produce a pharmacologic effect when administered orally, other cosol- PREMIXES vents, such as glycerin and propylene glycol, should be used to minimize the amount of alcohol required. To be designated Premixes are mixtures of one or more drug substances with as an , however, the solution must contain alcohol. suitable vehicles. Premixes are intended for admixture to animal feedstuffs before administration. They are used to facilitate di- lution of the active drug components with animal feed. Premix- Topical Solutions es should be as homogeneous as possible. It is essential that materials of suitable fineness be used and that thorough mixing Topical Solutions are solutions, usually aqueous but often be achieved at all stages of premix preparation. Premixes may containing other solvents, such as alcohol and polyols, intend- be prepared as powder, pellets, or in granulated form. The ed for topical application to the skin, or as in the case of Lido- granulated form is free-flowing and free from aggregates. caine Oral Topical Solution, to the oral mucosal surface. The term ‘‘’’ is applied to solutions or suspensions applied topically. SOLUTIONS Otic Solutions Solutions are liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a Otic Solutions, intended for instillation in the outer , are suitable solvent or mixture of mutually miscible solvents. Since aqueous, or they are solutions prepared with glycerin or other Revision In-Process molecules in solutions are uniformly dispersed, the use of solu- solvents and dispersing agents (e.g., Antipyrine and Benzocaine tions as dosage forms generally provides for the assurance of Otic Solution and Neomycin and Polymyxin B and Hydro- uniform dosage upon administration, and good accuracy when cortisone Otic Solution). diluting or otherwise mixing solutions. Substances in solutions, however, are more susceptible to chemical instability than the solid state and dose for dose, gen- erally require more bulk and weight in packaging relative to sol-

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1268 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

Ophthalmic Solutions eign odors. Aromatic waters may be prepared by distillation or solution of the aromatic substance, with or without the use of a See Ophthalmic Preparations. dispersing agent. Aromatic waters require protection from intense light and ex- cessive heat. Spirits Spirits are alcoholic or hydroalcoholic solutions of volatile SUPPOSITORIES substances prepared usually by simple solution or by admixture of the ingredients. Some spirits serve as flavoring agents while Suppositories are solid bodies of various weights and shapes, others have medicinal value. Reduction of the high alcoholic adapted for introduction into the rectal, vaginal, or urethral or- content of spirits by admixture with aqueous preparations often ifice of the . They usually melt, soften, or dissolve at causes . body temperature. A may act as a protectant or Spirits require storage in tight, light-resistant containers to palliative to the local tissues at the point of introduction or as prevent loss by evaporation and to limit oxidative changes. a carrier of therapeutic agents for systemic or local action. Sup- pository bases usually employed are cocoa , glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene Tinctures glycols of various molecular weights, and esters of polyethylene glycol. Tinctures are alcoholic or hydroalcoholic solutions prepared The suppository base employed has a marked influence on from vegetable materials or from chemical substances. the release of the active ingredient incorporated in it. While co- The proportion of drug represented in the different chemical coa butter melts quickly at body temperature, it is immiscible tinctures is not uniform but varies according to the established with body fluids and this inhibits the diffusion of fat-soluble standards for each. Traditionally, tinctures of potent vegetable drugs to the affected sites. Polyethylene glycol is a suitable base drugs essentially represent the activity of 10 g of the drug in for some antiseptics. In cases where systemic action is expected, each 100 mL of , the potency being adjusted following it is preferable to incorporate the ionized rather than the non- assay. Most other vegetable tinctures represent 20 g of the re- ionized form of the drug, in order to maximize bioavailability. spective vegetable material in each 100 mL of tincture. Although nonionized drugs partition more readily out of water- miscible bases such as glycerinated gelatin and polyethylene glycol, the bases themselves tend to dissolve very slowly and PROCESS P thus retard release in this manner. Oleaginous vehicles such as cocoa butter are seldom used in vaginal preparations be- Carefully mix the ground drug or mixture of drugs with a suf- cause of the nonabsorbable residue formed, while glycerinated ficient quantity of the prescribed solvent or solvent mixture to gelatin is seldom used rectally because of its slow dissolution. render it evenly and distinctly damp, allow it to stand for 15 Cocoa butter and its substitutes (Hard Fat) are superior for allay- minutes, transfer it to a suitable percolator, and pack the drug ing irritation, as in preparations intended for treating internal firmly. Pour on enough of the prescribed solvent or solvent mix- hemorrhoids. ture to saturate the drug, cover the top of the percolator, and, when the liquid is about to drip from the percolator, close the lower orifice and allow the drug to macerate for 24 hours or for Cocoa Butter Suppositories the time specified in the monograph. If no assay is directed, al- low the percolation to proceed slowly, or at the specified rate, Suppositories having cocoa butter as the base may be made gradually adding sufficient solvent or solvent mixture to pro- by means of incorporating the finely divided medicinal sub- duce 1000 mL of tincture, and mix (for definitions of flow rates, stance into the solid oil at room temperature and suitably shap- see under Extracts and Fluidextracts). If an assay is directed, col- ing the resulting mass, or by working with the oil in the melted lect only 950 mL of percolate, mix this, and assay a portion of it state and allowing the resulting suspension to cool in molds. A as directed. Dilute the remainder with such quantity of the pre- suitable quantity of hardening agents may be added to coun- scribed solvent or solvent mixture as calculation from the assay teract the tendency of some medicaments such as chloral hy- indicates is necessary to produce a tincture that conforms to the drate and phenol to soften the base. It is important that the prescribed standard, and mix. finished suppository melt at body temperature. The approximate weights of suppositories prepared with co- coa butter are given below. Suppositories prepared from other PROCESS M bases vary in weight and generally are heavier than the weights indicated here. Macerate the drug with 750 mL of the prescribed solvent or Rectal Suppositories for adults are tapered at one or both ends solvent mixture in a container that can be closed, and put in a and usually weigh about 2 g each. warm place. Agitate it frequently during 3 days or until the sol- Vaginal Suppositories are usually globular or oviform and uble is dissolved. Transfer the mixture to a filter, and weigh about 5 g each. They are made from water-soluble or wa- when most of the liquid has drained away, wash the residue ter-miscible vehicles such as polyethylene glycol or glycerinated on the filter with a sufficient quantity of the prescribed solvent gelatin. or solvent mixture, combining the filtrates, to produce 1000 mL Suppositories with cocoa butter base require storage in well- of tincture, and mix. closed containers, preferably at a temperature below 308 (con- Tinctures require storage in tight, light-resistant containers, trolled room temperature). away from direct sunlight and excessive heat.

Cocoa Butter Substitutes Waters, Aromatic Fat-type suppository bases can be produced from a variety of Aromatic waters are clear, saturated aqueous solutions (un- vegetable oils, such as coconut or palm kernel, which are mod- less otherwise specified) of volatile oils or other aromatic or vol- ified by esterification, hydrogenation, and fractionation to ob- atile substances. Their odors and are similar, respectively, tain products of varying composition and melting temperatures to those of the drugs or volatile substances from which they are (e.g., Hydrogenated Vegetable Oil and Hard Fat). These products prepared, and they are free from empyreumatic and other for- can be so designed as to reduce rancidity. At the same time, desired characteristics such as narrow intervals between melt- In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1269 ing and solidification temperatures, and melting ranges to ac- otic administration. These may be of two types, ready to use or commodate various formulation and climatic conditions, can intended for constitution with a prescribed amount of Water for be built in. Injection or other suitable diluent before use by the designated route. Suspensions should not be injected intravenously or in- trathecally. Glycerinated Gelatin Suppositories Suspensions intended for any route of administration should contain suitable antimicrobial agents to protect against bacte- Medicinal substances may be incorporated into glycerinated ria, yeast, and mold contamination (see Emulsions for some gelatin bases by addition of the prescribed quantities to a vehi- consideration of antimicrobial preservative properties that ap- cle consisting of about 70 parts of glycerin, 20 parts of gelatin, ply also to Suspensions). By its very nature, the particular matter and 10 parts of water. in a suspension may settle or sediment to the bottom of the Glycerinated gelatin suppositories require storage in tight container upon standing. Such may also lead containers, preferably at a temperature below 358. to caking and solidification of the sediment with a resulting dif- ficulty in redispersing the suspension upon agitation. To pre- vent such problems, suitable ingredients that increase Polyethylene Glycol–Base Suppositories viscosity and the gel state of the suspension, such as clays, sur- factants, polyols, polymers, or sugars, should be added. It is im- Several combinations of polyethylene glycols having melting portant that suspensions always be shaken well before use to temperatures that are above body temperature have been used ensure uniform distribution of the solid in the vehicle, thereby as suppository bases. Inasmuch as release from these bases de- ensuring uniform and proper dosage. Suspensions require stor- pends on dissolution rather than on melting, there are signifi- age in tight containers. cantly fewer problems in preparation and storage than exist with melting-type vehicles. However, high concentrations of higher-molecular-weight polyethylene glycols may lengthen Oral Suspensions dissolution time, resulting in problems with retention. Labels on polyethylene glycol suppositories should contain directions Oral Suspensions are liquid preparations containing solid par- that they be moistened with water before inserting. Although ticles dispersed in a liquid vehicle, with suitable flavoring they can be stored without refrigeration, they should be pack- agents, intended for oral administration. Some suspensions la- aged in tightly closed containers. beled as ‘‘’’ or ‘‘Magmas’’ fall into this category.

Surfactant Suppository Bases Topical Suspensions Several nonionic surface-active agents closely related chemi- Topical Suspensions are liquid preparations containing solid cally to the polyethylene glycols can be used as suppository ve- particles dispersed in a liquid vehicle, intended for application hicles. Examples of such surfactants are polyoxyethylene to the skin. Some suspensions labeled as ‘‘Lotions’’ fall into this sorbitan fatty acid esters and the polyoxyethylene stearates. category. These surfactants are used alone or in combination with other suppository vehicles to yield a wide range of melting tempera- tures and consistencies. One of the major advantages of such Otic Suspensions vehicles is their water-dispersibility. However, care must be tak- en with the use of surfactants, because they may either increase Otic Suspensions are liquid preparations containing micron- the rate of drug absorption or interact with drug molecules, ized particles intended for instillation in the outer ear. causing a decrease in therapeutic activity. Ophthalmic Suspensions Tableted Suppositories or Inserts See Ophthalmic Preparations. Vaginal suppositories occasionally are prepared by the com- pression of powdered materials into a suitable shape. They are prepared also by encapsulation in soft gelatin. SYRUPS See Oral Solutions. SUSPENSIONS Suspensions are liquid preparations that consist of solid par- SYSTEMS ticles dispersed throughout a liquid phase in which the particles are not soluble. Dosage forms officially categorized as ‘‘Suspen- In recent years, a number of dosage forms have been devel- sions’’ are designated as such if they are not included in other oped using modern technology that allows for the uniform re- more specific categories of suspensions, such as Oral Suspen- lease or targeting of drugs to the body. These products are sions, Topical Suspensions, etc. (see these other categories). commonly called delivery systems. The most widely used of Some suspensions are prepared and ready for use, while others these are Transdermal Systems. are prepared as solid mixtures intended for constitution just be- fore use with an appropriate vehicle. Such products are desig- nated ‘‘for Oral Suspension’’, etc. The term ‘‘Milk’’ is sometimes Transdermal Systems used for suspensions in aqueous vehicles intended for oral ad- ministration (e.g., Milk of Magnesia). The term ‘‘Magma’’ is of- Transdermal systems are self-contained, dis- ten used to describe suspensions of inorganic solids such as crete dosage forms that, when applied to intact skin, are de- Revision In-Process clays in water, where there is a tendency for strong hydration signed to deliver the drug(s) through the skin to the systemic and aggregation of the solid, giving rise to gel-like consistency circulation. Systems typically comprise an outer covering (bar- and thixotropic rheological behavior (e.g., Bentonite Magma). rier), a drug reservoir, which may have a rate-controlling The term ‘‘Lotion’’ has been used to categorize many topical membrane, a contact applied to some or all parts of suspensions and emulsions intended for application to the skin the system and the system/skin interface, and a protective liner (e.g., Calamine Lotion). Some suspensions are prepared in sterile that is removed before applying the system. The activity of form and are used as Injectables, as well as for ophthalmic and

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1270 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

these systems is defined in terms of the release rate of the gredients and formerly were intended for use in making pre- drug(s) from the system. The total duration of drug release from parations for hypodermic injection. They are employed orally, the system and the system surface area may also be stated. or where rapid drug availability is required such as in the case Transdermal drug delivery systems work by diffusion: the of Nitroglycerin Tablets, sublingually. drug diffuses from the drug reservoir, directly or through the Buccal tablets are intended to be inserted in the buccal rate-controlling membrane and/or contact adhesive if present, pouch, and sublingual tablets are intended to be inserted be- and then through the skin into the general circulation. Typical- neath the tongue, where the active ingredient is absorbed di- ly, modified-release systems are designed to provide drug deliv- rectly through the oral mucosa. Few drugs are readily absorbed ery at a constant rate, such that a true steady-state blood in this way, but for those that are (such as nitroglycerin and cer- concentration is achieved and maintained until the system is re- tain steroid hormones), a number of advantages may result. moved. At that time, blood concentration declines at a rate Soluble, effervescent tablets are prepared by compression consistent with the of the drug. and contain, in addition to active ingredients, mixtures of acids Transdermal drug delivery systems are applied to body areas (, tartaric acid) and sodium bicarbonate, which re- consistent with the labeling for the product(s). As long as drug lease carbon dioxide when dissolved in water. They are intend- concentration at the system/skin interface remains constant, ed to be dissolved or dispersed in water before administration. the amount of drug in the dosage form does not influence plas- Effervescent tablets should be stored in tightly closed con- ma concentrations. The functional lifetime of the system is de- tainers or moisture-proof packs and labeled to indicate that fined by the initial amount of drug in the reservoir and the they are not to be swallowed directly. release rate from the reservoir. NOTE—Drugs for local rather than systemic effect are com- monly applied to the skin embedded in glue on a cloth or plas- Chewable Tablets tic backing. These products are defined traditionally as plasters or tapes. Chewable tablets are formulated and manufactured so that they may be chewed, producing a pleasant tasting residue in the oral cavity that is easily swallowed and does not leave a bit- Ocular System ter or unpleasant aftertaste. These tablets have been used in formulations for children, especially multivitamin formu- Another type of system is the ocular system, which is intend- lations, and for the administration of antacids and selected an- ed for placement in the lower conjunctival fornix from which tibiotics. Chewable tablets are prepared by compression, the drug diffuses through a membrane at a constant rate usually utilizing mannitol, sorbitol, or sucrose as binders and fil- (e.g., Pilocarpine Ocular System). lers, and containing colors and flavors to enhance their appear- ance and taste. Intrauterine System Preparation of Molded Tablets An intrauterine system, based on a similar principle but in- tended for release of drug over a much longer period of time, Molded tablets are prepared from mixtures of medicinal sub- e.g., one year, is also available (e.g., Intrauterine stances and a diluent usually consisting of and pow- Contraceptive System). dered sucrose in varying proportions. The powders are dampened with solutions containing high percentages of alco- hol. The concentration of alcohol depends upon the solubility TABLETS of the active ingredients and fillers in the solvent system and the desired degree of hardness of the finished tablets. The damp- Tablets are solid dosage forms containing medicinal sub- ened powders are pressed into molds, removed, and allowed stances with or without suitable diluents. They may be classed, to dry. Molded tablets are quite friable and care must be taken according to the method of manufacture, as compressed tab- in packaging and dispensing. lets or molded tablets. The vast majority of all tablets manufactured are made by compression, and compressed tablets are the most widely used Formulation of Compressed Tablets dosage form in this country. Compressed tablets are prepared by the application of high pressures, utilizing steel punches and Most compressed tablets consist of the active ingredient and dies, to powders or granulations. Tablets can be produced in a a diluent (filler), , disintegrating agent, and lubricant. Ap- wide variety of sizes, shapes, and surface markings, depending proved FD&C and D&C dyes or lakes (dyes adsorbed onto in- upon the design of the punches and dies. Capsule-shaped tab- soluble aluminum hydroxide), flavors, and sweetening agents lets are commonly referred to as caplets. Boluses are large tab- may also be present. Diluents are added where the quantity lets intended for veterinary use, usually for large animals. of active ingredient is small or difficult to compress. Common Molded tablets are prepared by forcing dampened powders tablet fillers include lactose, starch, dibasic calcium phosphate, under low pressure into die cavities. Solidification depends up- and microcrystalline cellulose. Chewable tablets often contain on crystal bridges built up during the subsequent drying pro- sucrose, mannitol, or sorbitol as a filler. Where the amount of cess, and not upon the compaction force. active ingredient is small, the overall tableting properties are Tablet triturates are small, usually cylindrical, molded or com- in large measure determined by the filler. Because of problems pressed tablets. Tablet triturates were traditionally used as dis- encountered with bioavailability of hydrophobic drugs of low pensing tablets in order to provide a convenient, measured water-solubility, water-soluble diluents are used as fillers for quantity of a potent drug for compounding purposes. Such these tablets. tablets are rarely used today. Hypodermic tablets are molded tablets made from completely and readily water-soluble in- In-Process Revision

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Binders give adhesiveness to the powder during the prelimi- Physical evidence of poor tablet quality is discussed under nary granulation and to the compressed tablet. They add to the Stability Considerations in Dispensing Practice h1191i. cohesive strength already available in the diluent. While binders may be added dry, they are more effective when added out of solution. Common binders include acacia, gelatin, sucrose, po- WEIGHT VARIATION AND CONTENT UNIFORMITY vidone, methylcellulose, carboxymethylcellulose, and hydro- lyzed starch pastes. The most effective dry binder is Tablets are required to meet a weight variation test (see Uni- microcrystalline cellulose, which is commonly used for this pur- formity of Dosage Units h905i) where the active ingredient com- pose in tablets prepared by direct compression. prises a major portion of the tablet and where control of weight A disintegrating agent serves to assist in the fragmentation of may be presumed to be an adequate control of drug content the tablet after administration. The most widely used tablet dis- uniformity. Weight variation is not an adequate indication of integrating agent is starch. Chemically modified and content uniformity where the drug substance comprises a rela- cellulose, alginic acid, microcrystalline cellulose, and cross- tively minor portion of the tablet, or where the tablet is sugar- linked povidone, are also used for this purpose. Effervescent coated. Thus, the Pharmacopeia generally requires that coated mixtures are used in soluble tablet systems as disintegrating tablets and tablets containing 50 mg or less of active ingredi- agents. The concentration of the disintegrating agent, method ent, comprising less than 50% by weight of the dosage-form of addition, and degree of compaction play a role in effective- unit, pass a content uniformity test (see Uniformity of Dosage ness. Units h905i), wherein individual tablets are assayed for actual Lubricants reduce during the compression and ejec- drug content. tion cycle. In addition, they aid in preventing adherence of tab- let material to the dies and punches. Metallic stearates, stearic acid, hydrogenated vegetable oils, and talc are used as lubri- DISINTEGRATION AND DISSOLUTION cants. Because of the nature of this function, most lubricants are hydrophobic, and as such tend to reduce the rates of tablet Disintegration is an essential attribute of tablets intended for disintegration and dissolution. Consequently, excessive con- administration by mouth, except for those intended to be centrations of lubricant should be avoided. Polyethylene glycols chewed before being swallowed and for some types of extend- and some lauryl salts have been used as soluble lubri- ed-release tablets. A disintegration test is provided (see Disinte- cants, but such agents generally do not possess optimal lubri- gration h701i), and limits on the times in which disintegration is cating properties, and comparatively high concentrations are to take place, appropriate for the types of tablets concerned, usually required. are given in the individual monographs. Glidants are agents that improve powder fluidity, and they For drugs of limited water-solubility, dissolution may be a are commonly employed in direct compression where no gran- more meaningful quality attribute than disintegration. A disso- ulation step is involved. The most effective glidants are the col- lution test (see Dissolution h711i) is required in a number of loidal pyrogenic silicas. monographs on tablets. In many cases, it is possible to correlate Colorants are often added to tablet formulations for esthetic dissolution rates with biological availability of the active ingre- value or for product identification. Both D&C and FD&C dyes dient. However, such tests are useful mainly as a means of and lakes are used. Most dyes are photosensitive and they fade screening preliminary formulations and as a routine quality- when exposed to light. The federal Food and Drug Administra- control procedure. tion regulates the colorants employed in drugs.

Coatings Manufacturing Methods Tablets may be coated for a variety of reasons, including pro- Tablets are prepared by three general methods: wet granula- tection of the ingredients from air, moisture, or light, masking tion, dry granulation (roll compaction or slugging), and direct of unpleasant tastes and odors, improvement of appearance, compression. The purpose of both wet and dry granulation is to and control of the site of drug release in the gastrointestinal improve flow of the mixture and/or to enhance its compressi- tract. bility. Dry granulation (slugging) involves the compaction of pow- ders at high pressures into large, often poorly formed tablet PLAIN COATED TABLETS compacts. These compacts are then milled and screened to form a granulation of the desired particle size. The advantage Classically, tablets have been coated with sugar applied from of dry granulation is the elimination of both heat and moisture aqueous suspensions containing insoluble powders such as in the processing. Dry granulations can be produced also by ex- starch, , talc, or titanium dioxide, suspended truding powders between hydraulically operated rollers to pro- by means of acacia or gelatin. For purposes of identification and duce thin cakes which are subsequently screened or milled to esthetic value, the outside coatings may be colored. The fin- give the desired granule size. ished coated tablets are polished by application of dilute solu- Excipients are available that allow production of tablets at tions of in solvents such as chloroform or powdered mix. high speeds without prior granulation steps. These directly Water-protective coatings consisting of substances such as shel- compressible excipients consist of special physical forms of sub- lac or cellulose acetate phthalate are often applied out of non- stances such as lactose, sucrose, dextrose, or cellulose, which aqueous solvents prior to application of sugar coats. Excessive possess the desirable properties of fluidity and compressibility. quantities should be avoided. Drawbacks of sugar coating in- The most widely used direct-compaction fillers are microcrystal- clude the lengthy time necessary for application, the need for line cellulose, anhydrous lactose, spray-dried lactose, compress- waterproofing, which also adversely affects dissolution, and the ible sucrose, and some forms of modified starches. Direct increased bulk of the finished tablet. These factors have resulted compression avoids many of the problems associated with in increased acceptance of film coatings. Film coatings consist wet and dry granulations. However, the inherent physical pro- of water-soluble or dispersible materials such as hydroxypropyl perties of the individual filler materials are highly critical, and methylcellulose, methylcellulose, hydroxypropylcellulose, car- minor variations can alter flow and compression characteristics boxymethylcellulose sodium, and mixtures of cellulose acetate Revision In-Process so as to make them unsuitable for direct compression. phthalate and polyethylene glycols applied out of nonaqueous or aqueous solvents. Evaporation of the solvents leaves a thin film that adheres directly to the tablet and allows it to retain the original shape, including grooves or identification codes.

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DELAYED-RELEASE TABLETS A dosage form is a combination of drug substances Where the drug may be destroyed or inactivated by the gas- and excipients to facilitate dosing, administration, and tric juice or where it may irritate the gastric mucosa, the use of ‘‘enteric’’ coatings is indicated. Such coatings are intended to delivery of the to the patient. The design and delay the release of the medication until the tablet has passed through the stomach. The term ‘‘delayed-release’’ is used for testing of all dosage forms target drug product quality.1 Pharmacopeial purposes, and the individual monographs in- clude tests and specifications for Drug release (see Drug Release A testing protocol must consider not only the physical, h724i)orDisintegration (see Disintegration h701i). chemical, and biological properties of the dosage form

EXTENDED-RELEASE TABLETS as appropriate but also the administration route and de- Extended-release tablets are formulated in such manner as to sireddosingregimen.Theinterrelationships of dosage make the contained medicament available over an extended period of time following ingestion. Expressions such as ‘‘pro- forms and routes of administration have been summa- longed-action,’’ ‘‘repeat-action,’’ and ‘‘sustained-release’’ have also been used to describe such dosage forms. However, the rized in the compendial taxonomy for pharmaceutical term ‘‘extended-release’’ is used for Pharmacopeial purposes, and requirements for Drug release typically are specified in the dosage forms (Figure 1).2 The organization of this general individual monographs. information chapter is by the physical attributes of each particular dosage form (Tier Two), generally without spe- &GENERAL CONSIDERATIONS cific reference to route of administration. Information specific to route of administration is given when needed. This chapter provides general descriptions of and def- Tests to ensure compliance with pharmacopeial stan- initions for drug products, or dosage forms, commonly dards for dosage form performance fall into one of the used to administer the drug substance [active pharma- following areas. ceutical ingredient (API)]. It discusses general principles involved in the manufacture or compounding of these dosage forms, and recommendations for proper use and storage. A glossary is provided as a resource on no- menclature.

1 In the United States, a drug with a name recognized in USP– NF must comply with compendial identity standards or be deemed adulterated, misbranded, or both. To avoid being deemed adulterated, such drugs also must comply with com- pendial standards for strength, quality, or purity, unless labeled to show all respects in which the drug differs. See the Federal Food, Drug, and Cosmetic Act (FDCA), Sections 501(b) and 502(e)(3)(b), and Food and Drug Administration (FDA) regu- lations at 21 CFR 299.5. In addition, to avoid being deemed misbranded, drugs recognized in USP–NF also must comply with compendial standards for packing and labeling, FDCA Sec- tion 502(g). ‘‘Quality’’ is used herein as suitable shorthand for all such compendial requirements. This approach also is consis- tent with U.S. and FDA participation in the International Con- ference on Harmonization (ICH). The ICH guideline on specifications, Q6A, notes that ‘‘specifications are chosen to confirm the quality of the drug substance and drug product. . .’’ and defines ‘‘quality’’ as ‘‘The suitability of either a drug sub- stance or drug product for its intended use. This term includes such attributes as identity, strength, and purity.’’ 2 Marshall K, Foster TS, Carlin HS, Williams RL. Development of a compendial taxonomy and glossary for pharmaceutical dos- age forms. Pharm Forum. 2003;29(5):1742–1752. In-Process Revision

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Dose Uniformity (see also Uniformity of Dosage Units forms requires careful evaluation of drug substance par- h905i)—Consistency in dosing for a patient or consumer ticle or droplet size, incorporation techniques, and excip- requires that the variation in the drug substance content ient properties. of each dosage unit be accurately controlled throughout Stability (see also Pharmaceutical Stability h1150i)— the manufactured batch or compounded lot of drug pro- Drug product stability involves the evaluation of chemi- duct. Uniformity of dosage units typically is demonstra- cal stability, physical stability, and performance over ted by one of two procedures: content uniformity or time. The chemical stability of the drug substance in weight variation. The procedure for content uniformity the dose form matrix must support the expiration dating requires the assay of drug substance content of individual for the commercially prepared dosage forms and a be- units, and that for weight variation uses the weight of the yond-use date for a compounded dosage form. Test pro- individual units to estimate their content. Weight varia- cedures for potency must be stability indicating (see tion may be used where the underlying distribution of Validation of Compendial Procedures h1225i). Degrada- drug substance in the blend is presumed to be uniform tion products should be quantified. In the case of dis- and well-controlled, as in solutions. In such cases the persed or emulsified systems, consideration must be content of drug substance may be adequately estimated given to the potential for settling or separation of the for- by the net weight. Content uniformity does not rely on mulation components. Any physical changes to the dos- the assumption of blend uniformity and can be applied in age form must be easily reversed (e.g., by shaking) prior all cases. Tablets and capsules are assigned a limit below to dosing or administration. In vitro release test proce- nPoesRevision In-Process which the weight variation procedure is not applicable. dures such as dissolution and disintegration provide a Successful development and manufacture of dosage measure of continuing consistency in performance over time (see Dissolution h711i, Disintegration h701i,and Drug Release h724i).

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route of administration (e.g., by injection—Particulate Bioavailability (see also In Vitro and In Vivo Evaluation Matter in Injections h788i, or mucosal—Particulate Matter of Dosage Forms h1088i, and Assessment of Drug Product in Ophthalmic Solutions h789i). Additionally, dosage Performance—Bioavailability, Bioequivalence, and Dissolu- forms intended for the inhalation route of administration tion h1090i)—Bioavailability is influenced by factors such must be monitored for particle size and spray pattern (for as the method of manufacture or compounding, particle a metered-dose inhaler or dry-powder inhaler) and drop- size, crystal form (polymorph) of the drug substance, the let size (for nasal sprays). Further information regarding properties of the excipients used to formulate the dosage administration routes and suggested testing can be form, and physical changes as the drug product ages. As- found in the Guide to General Chapters, Charts 4–8 and surance of consistency in bioavailability over time (bio- 10–13. equivalence) requires close attention to all aspects of An appropriate manufacturing process and testing re- the production (or compounding) and testing of the gimen help ensure that a dosage form can meet the ap- dosage form. In vitro release (disintegration and dissolu- propriate quality attributes for the intended route of tion) testing is commonly used as a surrogate to demon- administration. strate consistent availability of the API from the formulated dosage. PRODUCT QUALITY TESTS, GENERAL Manufacture—Although detailed instructions about the manufacture of any of these dosage forms are be- ICH Guidance Q6A (available at www.ich.org) recom- yond the scope of this general information chapter, gen- mends specifications (list of tests, references to analytical eral manufacturing principles have been included, as well procedures, and acceptance criteria) to ensure that com- as suggested testing for proper use and storage. Further mercialized drug products are safe and effective at the information relative to extemporaneous compounding time of release and over their shelf life. Tests that are uni- of dosage forms can be found in Pharmaceutical Com- versally applied to ensure safety and efficacy (and pounding—Nonsterile Preparations h795i and Pharmaceu- strength, quality, and purity) include description, identi- tical Compounding—Sterile Preparations h797i. fication, assay, and impurities. Route of Administration—The primary routes of Description—According to the ICH guidance a qual- administration for pharmaceutical dosage forms can be itative description (size, shape, color, etc.) of the dosage defined as mucosal, oral, parenteral (by injection), inha- form should be provided. The acceptance criteria should lation, and topical/dermal, and each has subcategories include the final acceptable appearance. If any of these as needed. Many tests employed to ensure quality gen- characteristics change during manufacturing or storage, erally are applied across all of the administration routes, a quantitative procedure may be appropriate. It specifies but some tests are specific for individual routes. For ex- the content or the label claim of the article. This param- ample, products intended for injection must be evaluat- eter is not part of the USP dosage form monograph be- ed for Sterility h71i and Pyrogen Test h151i,andthe cause it is product specific. USP monographs define the manufacturing process (and sterilization technique) em- product by specifying the range of acceptable assayed ployed for parenterals (by injection) should ensure com- content of the active substance(s) present in the dosage pliance with these tests. Tests for particulate matter may form, together with any additional information about be required for solution dosage forms depending on the the presence or absence of other components, excipi- ents, or adjuvants. In-Process Revision

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evaluated by tests in API and excipients monographs. Im- Identification—Identification tests are discussed in purities arising from degradation of the drug substance the General Notices and Requirements. Identification tests or from the drug-product manufacturing process should should establish the identity of the drug or drugs present be monitored. Residual Solvents h467i is applied to all in the drug product and should discriminate between products where relevant. compounds of closely related structure that are likely to In addition to the universal tests listed above, the fol- be present. Identification tests should be specific for the lowing tests may be considered on a case-by-case basis. drug substances. The most conclusive test for identity is Physicochemical Properties—Examples include pH the infrared absorption spectrum (see Spectrophotometry h791i, Viscosity h911i, and Specific Gravity h841i. and Light- h851i and Spectrophotometric Identi- Particle Size—Forsomedosageforms,particlesize fication Tests h197i). If no suitable infrared spectrum can can have a significant effect on dissolution rates, bioavail- be obtained, other analytical methods can be used. ability, therapeutic outcome, and stability. Procedures Near-infrared (NIR) or Raman spectrophotometric meth- such as Aerosols, Nasal Sprays, Metered-Dose Inhalers, ods also could be acceptable as the sole identification and Dry Powder Inhalers h601i, and Particle Size Distribu- method of the drug product formulation (see Near- tion Estimation by Analytical Sieving h786i could be used. infrared Spectrophotometry h1119i and Raman Spectrosco- py h1120i). Identification by a chromatographic reten- Uniformity of Dosage Units—See discussion of tion time from a single procedure is not regarded as dose uniformity above. specific. The use of retention times from two chromato- Water Content—A test for water content is included graphic procedures for which the separation is based on when appropriate (see Water Determination h921i). different principles or a combination of tests in a single Microbial Limits—The type of microbial test(s) and procedure can be acceptable (see Chromatography acceptance criteria are based on the nature of the drug h621i and Thin-Layer Chromatographic Identification Test substance, method of manufacture, and the route of ad- h201i). ministration (see Microbiological Examination of Nonsterile

Assay—A specific and stability-indicating test should Products: Microbial Enumeration Tests h61i and Microbio- be used to determine the strength (API content) of the logical Examination of Nonsterile Products: Tests for Speci- drug product. Some examples of these procedures are fied Microorganisms h62i). —Microbial Assays h81i, Chromatography Antimicrobial Preservative Content—Accep- h621i,orAssay for Steroids h351i. In cases when the use tance criteria for preservative content in multidose prod- of a nonspecific assay is justified, e.g., Titrimetry h541i, ucts should be established. They are based on the levels other supporting analytical procedures should be used of antimicrobial preservative necessary to maintain the to achieve specificity. When evidence of inter- product’s microbiological quality at all stages through- ference with a nonspecific assay exists, a procedure with out its proposed usage and shelf life (see Antimicrobial Ef- demonstrated specificity should be used. fectiveness Testing h51i).

Impurities—Process impurities, synthetic by- Antioxidant Preservative Content—If antioxidant Revision In-Process products, and other inorganic and organic impurities preservatives are present in the drug product, tests of may be present in the API and excipients used in the their content should be performed. manufacture of the drug product. These impurities are

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DOSAGE FORMS Sterility—Depending on the route of administra- tion—e.g., ophthalmic preparations, implants, and solu- Aerosols tions for injection—sterility of the product is demonstrated as appropriate (see Sterility Tests h71i). Aerosols are preparations packaged under pressure and contain therapeutic agent(s) and a propellant that Dissolution—A test to measure release of the drug are released upon activation of an appropriate valve sys- substance(s) from the drug product normally is included tem. Upon activation of the valve system, the drug sub- for dosage forms such as tablets, capsules, suspensions, stance is released as a plume of fine particles or droplets. granules for suspensions, implants, transdermal delivery Only one dose is released from the preparation upon ac- systems, and medicated chewing gums. Single-point tivation of a metered valve. In the case of topical prod- measurements typically are used for immediate-release ucts, activation of the valve results in a continuous dosage forms. For modified-release dosage forms, appro- release of the formulation. priate test conditions and sampling procedures are es- In this chapter, the aerosol dosage form refers only to tablished as needed (see Dissolution h711i and Drug those products packaged under pressure that release a Release h724i). In some cases, dissolution testing may fine mist of particles or droplets when activated (see Glos- be replaced by disintegration testing (see Disintegration sary). Other products that produce dispersions of fine h701i). droplets or particles will be covered in subsequent sec- Hardness and Friability—These parameters are tions (e.g., Dry Powder Inhalers and Sprays). evaluated as in-process controls. Acceptance criteria de- pend on packaging, supply chain, and intended use (see

Tablet Friability h1216i and Tablet Breaking Force h1217i). TYPICAL COMPONENTS Extractables—When evidence exists that extracta- Typical components of aerosols are the formulation bles from the container-closure systems (e.g., rubber containing one or more drug substances and propellant, stopper, cap liner, or plastic ) have an impact on the container, the valve, and the actuator. Each compo- the safety or efficacy of the drug product, a test is includ- nent plays a role in determining various characteristics of ed to evaluate the presence of extractables and leach- the emitted plume, such as droplet or particle size distri- ables. bution, uniformity of delivery of the therapeutic agent, Depending on the type and composition of the dosage delivery rate, and plume velocity and geometry. The me- form, other tests such as alcohol content, redispersibility, tering valve and actuator act in tandem to generate the particle size distribution, rheological properties, reconsti- plume of droplets or particles. The metering valve allows tution time, endotoxins/pyrogens, particulate matter, measure of an accurate volume of the liquid formulation functionality testing of delivery systems, and osmolarity under pressure within the container. The activator directs may be necessary. the metered volume to a small orifice that is open to the atmosphere. Upon activation, the formulation is forced through the opening, forming the fine mist of particles that are directed to the site of administration. In-Process Revision

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Aerosol preparations may consist of either a two-phase Inhalation aerosols are intended to produce fine parti- (gas and liquid) or a three-phase (gas, liquid, and solid or cles or droplets for inhalation through the mouth and de- liquid) formulation. The two-phase formulation consists position in the pulmonary tree. The design of the delivery of drug(s) dissolved in liquefied propellant. Liquid co- system releases one dose with each actuation. These solvents, such as alcohol, propylene glycol, and polyeth- products are commonly known as metered-dose inhal- ylene glycols often are added to enhance the solubility of ers. the drug substance(s). Three phase inhalation and nasal Nasal aerosols produce fine particles or droplets for in- aerosol systems consist of a suspension or emulsion of halation through the nasal vestibule and deposition in the drug substance(s) [i.e., API(s)] in addition to the va- the nasal cavity. One dose is released with each activation porizable propellants. The suspension or emulsion of the of the valve. finely divided drug substance typically is dispersed in the Lingual aerosols are intended to produce fine particles liquid propellant with the aid of suitable biocompatible or droplets for deposition in the mouth. The design of surfactants or other excipients. the delivery system releases one dose with each actua- Propellants for aerosol formulations are typically low tion. molecular weight hydrofluorocarbons or hydrocarbons Topical aerosols produce fine particles or droplets for that are liquid when constrained in the container, exhibit application to the skin. Formulations that are intended a suitable vapor pressure at room temperature, and are for inhalation, nasal, or lingual administration are typical- biocompatible and nonirritating. Compressed gases do ly aqueous based, but topical aerosols may utilize nonaq- not supply a constant pressure over use and typically ueous solvents to achieve rapid drying or are not employed as propellants. action for abraded skin surfaces. Metal containers can withstand the vapor pressure produced by the propellant and reduce the opportunity PACKAGING that leachable components will enter the formulation. Excess formulation may be added to the container to en- The accuracy of a system’s delivered dose is demon- sure that the full number of labeled doses can be ac- strated at the range of pressures likely to be encountered curately administered. The container and closure must as a result of ambient temperature variations or storage be able to withstand the pressures anticipated under nor- in a refrigerator. As an alternative, the system should in- mal use conditions as well as when the system is exposed clude clear instructions for use to ensure the container to elevated temperatures. and contents have been equilibrated to room tempera- ture prior to use.

TYPES OF AEROSOL DOSAGE FORMS

LABELING FOR PROPER USE Aerosol dosage forms can be delivered via various routes. The design of the container and metering valve, Typical warning statements include:

as well as the formulation, are designed to target the site Contents under pressure. Do not puncture or incin- Revision In-Process of administration. erate container. Do not expose to heat or store at temperatures above 498.

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Keep out of the reach of children unless otherwise in dry-filled capsules, undesired interactions may be prescribed. more likely to occur (including gelatin crosslinking and Use only as directed; intentional misuse by deliberate pellicle formation).

concentration and inhaling of the contents can be Modified-Release Capsules—The release of APIs harmful or fatal. from capsules can be modified in several ways, including Many experts recommend the addition of a statement coating the filled capsule shells or the contents in the indicating that patients and/or consumers should seek case of dry-filled capsules. advice and instruction from a health care professional Delayed-Release Capsules—Capsules sometimes about the proper use of the device. are formulated to include enteric-coated granules to pro- tect acid-labile APIs from the gastric environment or to Capsules prevent adverse events such as irritation. Enteric-coated

Capsules are solid dosage forms in which the API and multiparticulate capsule dosage forms may reduce vari- excipients are enclosed within a soluble container or ability in bioavailability associated with gastric emptying shell. The shells may be composed of two pieces, a body times for larger particles (i.e., tablets) and to minimize and a cap, or they may be composed of a single piece. the likelihood of a therapeutic failure when coating de- Two-piece capsules are commonly referred to as hard- fects occur during manufacturing. shell capsules, and one-piece capsules are often referred to as soft-shell capsules. This distinction, although it is PREPARATION imprecise, reflects differing levels of plasticizers in the two compositions and the fact that one-piece capsules Two-Piece Capsules—Two-piece gelatin capsules us- typically are more pliable than two-piece capsules. ually are formed from blends of that have rela- The shells of capsules usually are made from gelatin. tively high gel strength in order to optimize shell clarity However, they also may be made from cellulose polymers and toughness or from hypromellose. They also may or other suitable material. Most capsules are designed for contain colorants such as D&C and FD&C dyes3 or vari- oral administration. ous iron oxides, opaquing agents such as titanium diox-

Two-Piece or Hard-Shell Capsules—Two-piece ide, dispersing agents, and preservatives. Gelatin capsule capsules consist of two telescoping cap and body pieces shells normally contain between 12% and 16% water. in a range of standard sizes.

One-Piece or Soft-Shell Capsules—One-piece cap- 3 In 1960 Congress enacted the Color Additive Amendments, sules typically are used to deliver an API as a solution or requiring FDA to regulate dyes, pigments, or other coloring agents in , drugs, and separately from food ad- suspension. Liquid formulations placed into one-piece ditives. Under the law, color additives are deemed unsafe unless they are used in compliance with FDA regulations. The law pro- capsules may offer advantages by comparison with dry- vides a framework for the listing and certification of color addi- tives. See FDCA section 721; see FDA regulations at 21 CFR Part filled capsules and tablets in achieving content uniformi- 70. Colors must also be listed in pertinent FDA regulations for specific uses; the list of color additives for drugs that are exempt ty of potent APIs or acceptable dissolution of APIs with from certification is published at 21 CFR Part 73, Subpart B. FDA also conducts a certification program for batches of color addi- poor aqueous solubility. Because the contact between tives that are required to be certified before sale; see 21 CFR Part 74 (Subpart B re: drugs). Regulations regarding certification the shell wall and its liquid contents is more intimate than procedures, general specifications, and the listing of certified provisionally listed colors, are at 21 CFR Part 80. FDA maintains a color additives website, with links to various legal and regula- tory resources, at: http://www.cfsan.fda.gov/~dms/col- toc.html In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1279

The shells are manufactured in one set of operations ethylene glycols now are more common. The physico- andlaterfilledinaseparatemanufacturingprocess. chemical properties of the vehicle can be chosen to Two-piece shell capsules are made by a process that in- ensure stability of the API as well as to influence the re- volves dipping shaped pins into gelatin or hypromellose lease profile from the capsule shell. solutions, followed by drying, cutting, and joining steps. Powder formulations for two-piece gelatin capsules Dry Powder Inhalers generally consist of the API and at least one excipient. The dry powder inhaler (DPI) consists of a mixture of Both the formulation and the method of filling can affect drug(s) and carrier, and all components exist in a finely release of the API. In the filling operation, the body and divided solid state packaged as a unit dose. The dose is cap of the shell are separated before filling. Following the released from the packaging by an appropriate mecha- filling operation, the machinery rejoins the body and cap nism and is mobilized into a fine mist only upon oral in- and ensures satisfactory closure of the capsule by exert- halation by the patient. ing appropriate force on the two pieces. The joined cap- sules can be sealed after filling by a band at the joint of the body and cap or by other suitable means. In com- TYPICAL COMPONENTS pounding prescription practice, two-piece capsules The basic components of the DPI are the formulation may be hand-filled. This permits the prescriber the consisting of the drug(s) and carrier, both in the dry choice of selecting either a single API or a combination state; packaging that contains an amount equivalent to of APIs at the exact dose level considered best for an in- a unit dose; and a mechanism designed to open the unit- dividual patient. dose container and permit mobilization of the powders One-Piece Capsules—One-piece shell capsules are by the patient inhaling through the built-in mouthpiece. formed, filled, and sealed in a single process on the same Typically, the unit-dose container is either a capsule machine and are available in a wide variety of sizes, made of gelatin or other suitable non-animal-derived shapes, and colors. The most common type of one-piece material (e.g., hypromellose or starch), or the container capsule is that produced by a rotary die process that re- may consist of a series of unit doses in foil-lined blisters sults in a capsule with a seam. The soft gelatin shell is arranged in a strip. When the drug is contained in a cap- somewhat thicker than that of two-piece capsules and sule, release of the medication takes place when the cap- is plasticized by the addition of polyols such as glycerin, sule is pierced. As a consequence of this release sorbitol, or other suitable material. The ratio of the plas- mechanism, the device is designed to minimize the gen- ticizer to the gelatin can be varied to change the flexibil- eration of capsule fragments that might subsequently be ity of the shell depending on the nature of the fill inhaled. When the drug is contained in a , the material, its intended usage, or environmental condi- mechanism is designed to advance an unused blister to a tions. platform where the foil lining can be peeled back to ex- In most cases, one-piece capsules are filled with liquids. pose the powder mixture to an air stream created when

Typically, APIs are dissolved or suspended in a liquid ve- Revision In-Process the patient inhales. To facilitate dosing compliance, hicle. Classically, an oleaginous vehicle such as a vegeta- some delivery devices incorporate dosing administration ble oil was used. However, nonaqueous, water-miscible information such as number of doses remaining. liquid vehicles such as the lower molecular weight poly-

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PACKAGING generally are described as either nonwashable or wash- able, reflecting the fact that an emulsion with an aqueous For drug contained in blister-pack strips, the packs external continuous phase is more easily removed than must be designed to allow individual blister cavities to one with a nonaqueous external phase (water-in-oil be opened without compromising the seal of adjacent emulsion). Where the term ‘‘cream’’ is used without cavities. Package components must provide acceptable qualification, a water-washable product is generally in- protection from humidity, light, and/or as appro- ferred. priate. Containers for DPIs typically are made of plastic, Lotions—Lotions are an emulsified liquid dosage form but metal may be suitable. Packaging for the encapsulat- generally intended for external application to the skin. ed drug must provide protection from humidity ex- Historically, some topical suspensions such as calamine tremes to ensure that capsule breakage will occur in lotion have been called lotions but that nomenclature the desired fashion. is not currently preferred. Lotions share many character- istics with creams. The distinguishing factor is that they LABELING AND USE are more fluid than semisolid and thus pourable. Due to

Typical warning statements include: their fluid character, lotions are more easily applied to Keep out of the reach of children unless otherwise large skin surfaces than semisolid preparations. Lotions prescribed. may contain antimicrobial agents as preservatives. Do not attempt to dissemble mechanism. Discard the device after all doses have been administered. PREPARATION Keep the device level while in use. Pharmaceutical Compounding—Nonsterile Preparations Do not breathe into the device. h795i provides general information regarding the prep- Many experts recommend the addition of a statement aration of emulsions. indicating that patients and/or consumers should seek advice and instruction from a health care professional Creams—Creams may be formulated from a variety of about the proper use of the device. oils, both mineral and vegetable, and from fatty alcohols, fatty acids, and fatty esters. The solid excipients are melt-

Emulsions (Creams and Lotions) ed at the time of preparation. Emulsifying agents include nonionic surfactants, , and . Soaps are Creams—Creams are semisolid emulsion dosage usually formed from a fatty acid in the oil phase hydro- forms. They often contain more than 20% water and vol- lyzed by a base dissolved in the aqueous phase in situ atiles and typically contain less than 50% hydrocarbons, during the preparation of creams. waxes, or polyols as the vehicle for the API. Creams gen- Preparation usually involves separating the formula erally are intended for external application to the skin or components into two portions: and aqueous. The to the mucous membranes. Creams have a relatively soft, lipid portion contains all water-insoluble components spreadable consistency and can be formulated as either a and the aqueous portion the water-soluble components. water-in-oil emulsion (e.g., or Fatty Cream as Both phases are heated to a temperature above the melt- in the European Pharmacopoeia)orasanoil-in-water ing point of the highest melting component. The phases emulsion (e.g., Valerate Cream). Creams then are mixed and the mixture is stirred until reaching In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1281 ambient temperature or the mixture has congealed. Mix- TYPE A MEDICATED ARTICLES ing generally is continued during the cooling process to Type A medicated articles are products containing one promote uniformity. Traditionally, the aqueous phase is or more animal APIs, and that are sold to licensed feed added to the lipid phase, but comparable results have mills or producers and are intended to be further diluted been obtained with the reverse procedure. High-shear by mixing into food or water prior to consumption by homogenation may be employed to reduce particle or the animals. Because these preparations are not actually droplet size and improve the physical stability of the re- dosed to animals, they are not considered dosage forms. sultant dosage form. The API(s) can be added to the phase in which it is sol- uble at the beginning of the manufacturing process, or it TYPE B MEDICATED FEEDS can be added after the cream is prepared by a suitable Type B medicated feeds are products that contain a dispersion process such as levigation or milling with a rol- type A medicated article, or another type B medicated ler mill. Creams usually require the addition of a preser- feed, plus a substantial quantity of nutrients (not less vative(s) unless they are compounded immediately prior than 25% of the total weight). Like type A medicated ar- to use and intended to be consumed in a relatively short ticles, type B medicated feeds are intended for mixture period of time. with food or water and additional nutrients, are not to Lotions—Lotions usually are prepared by dissolving or be fed directly to the animals, and are not considered dispersing the API into the more appropriate phase (oil or dosage forms. water), adding the appropriate emulsifying or suspend- ing agents, and mixing the oil and water phases to form a uniform fluid emulsion. TYPE C MEDICATED FEEDS

Type C medicated feeds are made from type A medi- cated articles or type B medicated feeds and are prepared LABELING AND PACKAGING at concentrations of the API appropriate for administra- Some products may require labeling directions indicat- tion to animals by mixing in food or water. Administra- ing to shake well prior to application and to avoid freez- tion of type C medicated feeds can be accomplished ing. Storage limits must be specifically indicated to by blending directly into the feed; top-dressing the prep- prevent melting of semisolid components. Instructions aration onto the animal’s normal daily rations; or heat- to ensure proper dosing and administration must accom- ing, steaming, and extruding into pellets that are pany the product. Tight containers are used for prepara- mixed or top-dressed onto the animal’s food. Another tion and storage to prevent loss by evaporation. form of type C medicated feeds is compressed or molded blocks from which animals receive the API or nutrients via Feed Additives licking the block.

Feed additives are preparations used in veterinary nPoesRevision In-Process medicine to deliver the API(s) via the water or food given to animals. The feed additive may be either a solid or liq- uid and sometimes is called a premix. Feed additives are further subdivided into three types.

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PREPARATION per bags, often with polyethylene liners, for solids and in plastic containers for liquids. Typical sizes are 50-lb bags Type A medicated articles that are liquids are produced or several-gallon containers. by mixing the API(s) with a suitable solvent (e.g., water or propylene glycol). The API(s) is usually dissolved to pro- Foams duce a solution, but suspension products also could be produced. Medicated foams are emulsions containing a dispersed Type A medicated articles that are solids are produced phase of gas bubbles in a liquid continuous phase con- by blending the API with excipients to provide a uniform taining the API. Medicated foams are packaged in pres- dosage form when mixed with the animal’s feed. Often surized containers or special dispensing devices and are the API is first mixed with an excipient (e.g., starch or so- intended for application to the skin or mucous mem- dium aluminosilicate) that has a similar particle size and branes. The medicated foam is formed at the time of ap- can help distribute the API uniformly throughout the final plication. Surfactants are used to ensure the dispersion of drug product. This pre-blend is then mixed with bulking the gas and the two phases. Medicated foams have a excipients (e.g., calcium carbonate or soybean hulls). fluffy, semisolid consistency and can be formulated to Mineral oil may be added to aid uniform distribution, break to a liquid quickly or to remain as foam to ensure to prevent particle segregation during shipping, and to prolonged contact. minimize formation of airborne API particles during pro- Medicated foams intended to treat severely injured duction of type B or C medicated feeds. skin or open wounds must be sterile. Type B or C medicated feeds are produced at licensed feed mills or by farm producers. Type A medicated arti- PREPARATION cles are added to the feeds (e.g., ground corn or oats) during the milling process of making feeds. Liquid type A foam may contain one or more APIs, surfactants, A medicated articles often are sprayed in at set rates, aqueous or nonaqueous liquids, and the propellants. If and solid type A medicated articles are added slowly to the propellant is in the internal (discontinuous) phase aid in creating uniform distribution in the feeds. Liquid (i.e., is of the oil-in-water type), a stable foam is dis- type A medicated articles can also be mixed in with bulk charged. If the propellant is in the external (continuous) water sources at prescribed amounts. phase (i.e., is of the water-in-oil type), a spray or a quick- breaking foam is discharged. Quick-breaking foams for- mulated with alcohol create a cooling sensation when LABELING AND PACKAGING applied to the skin and may have disinfectant properties. Type A medicated articles or type B medicated feeds include special labeling to indicate that they should be LABELING AND USE used in the manufacture of animal feeds or added to the drinking water. The labels indicate that they are not Foams formulated with flammable components should to be fed directly to animals. Also included is a statement be appropriately labeled. Labeling indicates that prior to indicating ‘‘Not for Human Use’’. Type A medicated arti- dispensing, a foam drug product is shaken well to ensure cles or type B medicated feeds are packaged either in pa- uniformity. The instructions for use must clearly note spe- In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1283 cial precautions that are necessary to preserve sterility. In SPECIAL CONSIDERATIONS the absence of a metering valve, delivered volume may The container and system fittings should be appropri- be variable. ate for the medical gas. Adaptors should not be used to connect containers to patient-use supply system piping Medical Gases (Inhalation Materials) or equipment. Large quantities of gases such as oxygen Medical gases are products that are administered di- or nitrogen can be stored in the liquid state in a cryogen- rectly as a gas. A medical gas has a direct pharmacolog- ic container and converted into a gas, as needed, by ical action or acts as a diluent for another medical gas. evaporation. Additional rules concerning the construc- Gases employed as excipients for administration of aero- tion and use of cryogenic containers are promulgated sol products, as an adjuvant in packaging, or produced by governmental agencies (e.g., U.S. Department of by other dosage forms, are not included in this definition. Commerce). Components—Medical gases may be single compo- Containers, tubing, and administration masks em- nents or defined mixtures of components. Mixtures also ployed for gases containing oxygen are free of any com- can be extemporaneously prepared at the point of use. pound that would be sensitive to oxidation or that would Administration—Medical gases may be adminis- be irritating to the respiratory tract. tered to the patient via the pulmonary route or via extra- A significant fraction of the dose of a medical gas may corporeal methods. The dose of medical gas typically is be released into the general vicinity of the patient due to metered by a volume rate of flow under ambient temper- incomplete absorption. Adequate ventilation may be ature and pressure conditions. Administration of a highly necessary to protect health care workers and others from compressed gas generally requires a regulator to de- exposure to the gas (e.g., ). crease the pressure, a variable-volume flow controller, and suitable tubing to conduct the gas to the patient. LABELING For pulmonary administration, the gas flow will be direct- Warning statements to be placed on pressurized con- ed to the nose or mouth by a suitable device or into the tainers include: trachea through a mechanical ventilator. When medical Contents under pressure. gases are administered chronically, provision for humid- Do not puncture or incinerate container. ification is common. Care should be exercised to avoid Do not expose to heat or store at temperatures microbial contamination. above 498. Keep out of the reach of children unless otherwise STORAGE prescribed.

Medical gases are stored in a compressed state in cyl- Use only as directed; intentional misuse may be inders or other suitable containers. The containers must harmful or fatal. be constructed of materials that can safely withstand the If required under the individual monograph, label to nPoesRevision In-Process expected pressure and must be impact resistant. In some indicate method of manufacture (such as oxygen via air cases each container holds a single defined dose (e.g., liquefaction). When piped directly from the storage con- general anesthetics), but in other cases the container tainer to the point of use, the gas must be labeled for holds sufficient gas for extended administration. content at each outlet.

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PREPARATION When oxygen is in use, a posted warning should indi- cate the necessity of extinguishing materials See Pharmaceutical Compounding—Nonsterile Prepara- and avoiding the use of open flames or other potential tions h795i for general procedures. Also see the informa- ignition sources. tion contained under Dosage Forms, Suspensions for the formulation and manufacture of gels containing inorgan- Gels ic components or APIs in the solid phase. See Pharmaceu- tical Compounding—Sterile Preparations h797i for general Gels (sometimes called jellies) are semisolid systems procedures for the preparation of sterile gels such as Lido- consisting either of suspensions of small inorganic parti- caine Hydrochloride Jelly. cles or of organic molecules interpenetrated by a liquid. Gels formed with large organic molecules may be Gels can be classed either as single-phase or two-phase formed by dispersing the molecule in the continuous systems. phase (e.g., by heating starch), by cross-linking the dis- A two-phase gel consists of a network of small discrete persed molecules by changing the pH (as for Carbomer particles (e.g., Aluminum Hydroxide Gel or Psyllium Hemi- Copolymer), or by reducing the continuous phase (as cellulose). In a two-phase system the gel mass sometimes for jellies formed with sucrose). is referred to as a magma (e.g., Bentonite Magma) if the Care should be taken to ensure uniformity of the APIs particle size of the suspended material is large. Both gels by dispersing them by vigorous mixing or milling or by and magmas may be thixotropic, forming semisolids on shaking if the preparation is less viscous. standing and becoming liquid on agitation. They should be shaken before use to ensure homogeneity and should

be so labeled (see Suspensions). PACKAGING AND STORAGE Single-phase gels consist of organic macromolecules Store in tight containers to prevent water loss. Avoid uniformly distributed throughout a liquid in such a man- freezing. ner that no apparent boundaries exist between the dis- persed macromolecules and the liquid. Single-phase Granules gels may be made from natural or synthetic macromole- cules (e.g., Carbomer, Hydroxypropyl Methylcellulose,or Granules are solid dosage forms that are composed of Starch) or natural gums (e.g., Tragacanth). The latter pre- agglomerations of smaller particles. These multicompo- parations are also called mucilages. Although these gels nent compositions are prepared for oral administration commonly are aqueous, alcohols and oils may be used as and are used to facilitate flexible dosing regimens, ad- the continuous phase. For example, mineral oil can be dress stability challenges, allow taste masking, or facili- combined with a polyethylene resin to form an oleagi- tate flexibility in administration (for instance, to nous ointment base. pediatric patients, geriatric patients, or animals). Granu- Gels can be administered by the topical or mucosal lar dosage forms may be formulated for direct oral ad- routes. Gels containing antibiotics administered by teat ministration and may facilitate compounding of infusion are often the dosage form used in veterinary multiple APIs by allowing compounding pharmacists to medicine to treat mastitis. blend various granular compositions in the retail or hos- pital pharmacy. More commonly, granules are reconsti- In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1285 tuted to a suspension by the addition of water or a sup- (e.g., buffers, antioxidants, or chelating agents) or to plied liquid diluent immediately prior to delivery to the provide color, sweetness, flavor, and for suspensions, ac- patient. Effervescent granules are formulated to liberate ceptable viscosity to ensure adequate suspension of the gas (carbon dioxide) upon addition of water. Common particulate to enable uniform dosing. examples of effervescent granules include antacid and Effervescent granules typically are formulated from so- potassium supplementation preparations. Common dium or potassium bicarbonate and an acid such as citric therapeutic classes formulated as granule dosage forms or tartaric acid. To prevent untimely generation of car- include antibiotics, certain laxatives (such as senna ex- bon dioxide, manufacturers should take special precau- tract products), electrolytes, and various cough and cold tions to limit residual water in the product due to remedies that contain multiple APIs. manufacture and to select packaging that protects the Granular dosages also are employed in veterinary med- product from moisture. The manufacture of effervescent icine when they are often placed on top of or mixed with granules can require specialized facilities designed to an animal’s food. They are frequently provided with a maintain very low humidity (approximately 10% relative measuring device to allow addition to feeds. The resul- humidity). Effervescent powder mixtures are purposely tant mix facilitates dosing. formed into relatively course granules to reduce the rate of dissolution and provide a more controlled efferves- cence. PREPARATION

Granules often are the precursors used in tablet com- PACKAGING AND STORAGE pression or capsule filling. Although this application rep- resents a pharmaceutical intermediate and not a final Granules for reconstitution may be packaged in unit- dosage form, numerous commercial products are based of-use containers or in containers with sufficient quan- on granules. In the typical manufacture of granules, the tities to accommodate a typical course of therapy (fre- API is blended with excipients (processing aids) and wet- quently 10 days to 2 weeks with products). ted with an appropriate pharmaceutical solvent or blend Packaging should provide suitable protection from mois- of solvents to promote agglomeration. This composition ture. This is particularly true for effervescent granules. is dried and sized to yield the desired material properties. Granules may be stored under controlled room temper- Frequently, granules are used because the API is unsta- ature conditions unless other conditions are specifically ble in aqueous environments and cannot be exposed to noted. water for periods sufficient to accommodate manufac- Many granule products specify refrigerated storage fol- ture, storage, and distribution in a suspension. Prepara- lowing reconstitution and direct the patient to discard tion of the liquid dosage form from the granules unused contents after a specified date that is based on immediately prior to dispensing allows acceptable stabil- the stability of the API in the reconstituted preparation. ity for the duration of use. Granules manufactured for this

purpose are packaged in quantities sufficient for a limited Revision In-Process LABELING AND USE time period—usually one course of therapy that typically does not exceed 2 weeks. In addition to the API, other Effervescent granules (and tablets) are labeled to indi- ingredients may be added to ensure acceptable stability cate that they are not to be swallowed directly.

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Reconstitution of granules must ensure complete wet- Medicated gums are formulated from insoluble synthetic ting of all ingredients and sufficient time and agitation to gum bases such as polyisoprene, polyisobutylene, isobu- allow the soluble components to dissolve. Specific in- tyleneisoprene copolymer, styrene butadiene rubber, structions for reconstitution provided by the manufactur- polyvinyl acetate, polyethylene, ester gums, or polyter- er should be carefully followed. penes. Plasticizers and softeners such as propylene gly- Reconstituted suspensions should be shaken before use col, glycerin, , or processed vegetable oils are to re-suspend the dispersed particulates. This is especially added to keep the gum base pliable and to aid incorpo- true of suspension preparations dosed from multiple- ration of the API(s), sweeteners, and flavoring agents. dose containers. For particularly viscous suspensions Sugars as well as artificial sweeteners and flavorings are prone to air entrapment, instructions may advise the user incorporated to improve taste, and dyes may be used how to shake the preparation to re-suspend settled par- to enhance appearance. Some medicated gums are coat- ticulates while minimizing air entrapment. ed with magnesium stearate to reduce tackiness and im- prove handling during packaging. A preservative may be added. SPECIAL CONSIDERATIONS

For granules reconstituted to form suspensions for oral PREPARATION administration, acceptable suspension of the particulate

phase depends on the particle size of the dispersed phase Melted Gum—The gum base is melted at a tempera- as well as the viscosity of the vehicle. Temperature can ture of about 1158 until it has the viscosity of thick syrup influence the viscosity, which influences suspension pro- and at that point is filtered through a fine-mesh screen. perties and the ease of removal of the dose from the bot- This molten gum base is transferred to mixing tanks tle. In addition, temperature cycling can lead to changes where the sweeteners, plasticizers, and typically the API in the particle size of the dispersed phase via Ostwald rip- are added and mixed. Colorings, flavorings, and preser- ening. Thus, clear instructions should be provided re- vatives are added and mixed while the melted gum is garding the appropriate storage temperature for the cooling. The cooled mixture is shaped by extrusion or product. rolling and cutting. Dosage units of the desired shape and potency are packaged individually. Additional coat- Medicated Gums ings such as powder coatings to reduce tackiness or film or sugar coatings may be added to improve taste or fa- Medicated gum is a semisolid confection that is de- cilitate bulk packaging. signed to be chewed rather than swallowed. Medicated gums release the API(s) into the saliva. Medicated gums Directly Compressed Gum—The gum base is sup- can deliver therapeutic agents for local action in the plied in a free-flowing granular powder form. The pow- mouth (such as antibiotics to control gum disease) or der gum base is then dry blended with sweeteners, for systemic absorption via the buccal or gastrointestinal flavors, the API, and lubricant. The blend is then pro- routes (e.g., or ). Most medicated gums cessed through a conventional tablet press and tableted are manufactured using the conventional melting pro- into desired shapes. The resulting medicated gum tablets cess derived from the confectionary industry or alterna- tively may be directly compressed from gum powder. In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1287 can be further coated with sugar or sugar-free excipients. excipient (matrix). Poly(lactide-co-glycolide) polymers These tablets can be packaged in blisters or as have been used frequently. These excipients typically re- needed. sorb by hydrolysis of ester linkages. The microparticles are administered by suspension in an aqueous vehicle fol- lowed by injection with a conventional and nee- SPECIAL CONSIDERATIONS dle. Release of the drug from the microparticles begins Medicated gums are typically dispensed in unit-dose after physiological fluid enters the matrix, dis- packaging. The patient instructions also may include a solving some of the drug that then is released by a diffu- caution to avoid excessive heat. sion-controlled process. Drug release also can occur as the matrix erodes. Implants Polymer implants can be formed as a single shaped mass such as a cylinder. The polymer matrix must be bio- Implants are long-acting dosage forms that provide compatible, but it can be either biodegradable or non-bi- continuous release of the API for periods of months to odegradable. Shaped polymer implants are administered years. They are administered by the parenteral route. by means of a suitable special injector. Release kinetics For systemic delivery they may be placed subcutane- typically are not zero-order, but zero-order kinetics are ously, or for local delivery they can be placed in a specific possible. Drug release can be controlled by the diffusion region in the body. of the API from the bulk polymer matrix or by the proper- Several types of implants are available. Pellet implants ties of a rate-limiting polymeric membrane coating. Poly- are small, sterile, solid masses composed of an API with or mer implants are used to deliver potent small molecules without excipients. They are usually administered by like steroids (e.g., estradiol for cattle) and large molecules means of a suitable special injector (e.g., trocar) or by like peptides [e.g., luteinizing hormone-releasing hor- surgical incision. Release of the API from pellets typically mone (LHRH)]. Example durations of drug release are 2 is controlled by diffusion and dissolution kinetics. The size and 3 months for biodegradable implants and 1 year of the pellets and rate of erosion will influence the release for non-biodegradable implants. An advantage of biode- rate, which typically follows first-order kinetics. Drug re- gradable implants is that they do not require removal af- lease from pellets for periods of 6 months or more is pos- ter release of all drug content. Non-biodegradable sible. Pellet implants have been used to provide polymer implants can be removed before or after drug extended delivery of hormones such as testosterone or release is complete or may be left in situ. An implant estradiol. can have a tab with a hole in it to facilitate suturing it Resorbable microparticles are a type of implants that in place, e.g., for an intravitreal implant for local ocular provide extended release of drug over periods varying delivery. Such implants may provide therapeutic release from a few weeks to months. They can be administered for periods as long as 2.5 years. subcutaneously or intramuscularly for systemic delivery, Some implants are designed to form as a mass in situ. or they may be deposited in a desired location in the

These implants are initially prepared as liquid formula- Revision In-Process body for site-specific delivery. Injectable resorbable mi- tions comprising polymer, API, and solvent for the poly- croparticles (or microspheres) generally range from 20 mer. The polymer solvent can be water or an organic to 100 mm in diameter. They are composed of a drug dis- solvent. After administration of the liquid formulation persed within a biocompatible, bioresorbable polymeric

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to a patient by subcutaneous or intramuscular adminis- PACKAGING AND STORAGE tration, it forms a gel or a solid polymeric matrix that All implants are individually packaged (typically in their traps the API and extends the API release for days or injector or for veterinary use in cartridges that are placed months. In situ-forming implants also are used for local in the injector guns), are sterile (except for some animal delivery of the API to treat periodontal disease. The im- health products), and conform to the appropriate stan- plant is formed within the periodontal pocket. dards for injection. Biodegradable implants are protected Another type of implant can be fabricated from a metal from moisture so the polymer does not hydrolyze and al- such as titanium and plastic components. These implants ter drug release kinetics before use. are administered by means of a suitable injector or by surgical installation. A solution of API inside the implant, Inserts like an LHRH solution, is released via an osmotically dri- ven pump inside the implant. Duration of release may Inserts are solid dosage forms that are inserted into a be as long as 1 year or more. Release kinetics are zero or- body cavity other than the rectum (see Suppositories). der. After the drug is delivered, metal-based implants are The API is delivered in inserts for local or systemic action. removed. Inserts applied to the eye, such as Pilocarpine Ocular Sys- Drug-eluting stents combine the mechanical effect of tem, typically are sterile. Vaginal inserts for humans are the stent to maintain arterial patency with the prolonged usually globular or oviform and weigh about 5 g each. pharmacologic effect of the incorporated API (to reduce Vaginal inserts for cattle are T-shaped, are formed of poly- restenosis, inhibit clot formation, or combat ). mer, are removable, and can be used for up to 8 days. As an example, a metal stent can be coated with a One veterinary application is for estrus synchronization. non-biodegradable or biodegradable polymer- Inserts intended to dissolve in vaginal secretions usually containing API. The resultant coating is a polymeric ma- are made from water-soluble or water-miscible vehicles trix that controls the extended release of the API. such as polyethylene glycol or glycerinated gelatin. Vagi- nal inserts such as dinoprostone vaginal insert (e.g., see USP monograph Dinoprostone Vaginal Suppositories)are PREPARATION formulated to deliver medication to the cervix and to Pellet implants are made by API compression or mold- be removed or recovered once the API has been released. ing. Cylindrical polymeric implants typically are made by Intrauterine inserts such as Progesterone Intrauterine Con- melt extrusion of a blend of API and polymer, resulting in traceptive System are used to deliver APIs locally to a rod that is cut into shorter lengths. Polymer implants achieve efficacy while reducing side effects. Some intra- also can be made by injection molding. Still other im- uterine inserts are formulated to remain in the uterus for plants are assembled from metal tubes and injection- extended periods of time. An intra-urethral insert of al- molded plastic components. prostadil is available for the treatment of erectile dysfunc- Sterility can be achieved by terminal sterilization or by tion. employing aseptic manufacturing procedures. In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1289

PREPARATION STORAGE AND LABELING

For general considerations see Pharmaceutical Com- Storage, packaging, and labeling consider the physical pounding—Nonsterile Preparations h795i. Inserts vary properties of the material and are designed to maintain considerably in their preparation. Inserts may be molded potency and purity. (using technology similar tothatemployedtoprepare lozenges, suppositories, or plastics), compressed from Lotions (see Emulsions) powders (as in tableting), or formulated as special appli- cations of capsules (soft gelatin capsules and hard gelatin Lozenges capsules have been employed for extemporaneously compounded preparations). Inserts may be formulated Lozenges are solid oral dosage forms that are designed to melt at body temperature or disintegrate upon inser- to dissolve or disintegrate slowly in the mouth. They con- tion. Design of the dosage form should take into consid- tain one or more APIs that are slowly liberated from the eration the fluid volume available at the insertion site and flavored and sweetened base. They are frequently in- minimize the potential to cause local irritation. Most in- tended to provide local action in the oral cavity or the serts are formulated to ensure retention at the site of ad- throat but also include those intended for systemic ab- ministration. sorption after dissolution. The typical therapeutic cate- gories of APIs delivered in lozenges are antiseptics, , , antitussives, and antibiotics. STORAGE AND LABELING Molded lozenges are called cough drops or pastilles. Appropriate storage conditions must be clearly indicat- Molded lozenges mounted on a stick are known as lolli- ed in the labeling for all inserts, especially for those that pops. Lozenges prepared by compression or by stamp- are designed to melt at body temperature. Instructions ing or cutting from a uniform bed of paste sometimes to ensure proper dosing and administration must accom- are known as troches. Troches are often produced in a pany the product. circular shape. Lozenges can be made using sugars such as sucrose Liquids and dextrose or can provide the benefits of a sugar-free formulation that is usually based on sorbitol or mannitol. As a dosage form a liquid consists of a pure chemical in Polyethylene glycols and hypromellose sometimes are in- its liquid state. Examples include mineral oil, isoflurane, cluded to slow the rate of dissolution. and ether. This dosage form term is not applied to solu- tions. In veterinary medicine liquids may be administered topically or diluted via mixing with drinking water or MANUFACTURE food. Excipients used in molded lozenge manufacture in- clude gelatin, fused sucrose, sorbitol, or another carbo-

hydrate base. Revision In-Process Molded lozenges using a sucrose or sorbitol base con- taining APIs such as phenol, , fenta- nyl, and dyclonine hydrochloride and menthol are

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1290 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

prepared by the sugar (sucrose, corn syrup, and PACKAGING AND STORAGE sorbitol)andwateratabout1508 to reduce the water Many lozenges are sensitive to moisture, and typically content to less than 2%. The molten sugar solution is a monograph indicates that the package or container transferred to a cooling belt or cooling table, and medic- type is well closed and/or moisture resistant. Storage in- aments, flavorings, and colorings are added and thor- structions may include protection from high humidity. oughly mixed while cooling. Individual dosage units of the desired shape are formed by filling the molten mass Ointments into molds. These lozenges are quickly cooled in the molds to trap the base in the glassy state. Once formed, Ointments are semisolid preparations intended for ex- the lozenges are removed from the molds and packaged. ternal application to the skin or mucous membranes. Care is taken to avoid excessive moisture during storage APIs delivered in ointments are intended for local action to prevent crystallization of the sugar base. or for systemic absorption. Ointments usually contain Compressed lozenges are made using excipients that less than 20% water and volatiles and more than 50% may include a filler, binder, sweetening agent, flavoring hydrocarbons, waxes, or polyols as the vehicle. Ointment agent, and lubricant. Sugars such as sucrose, sorbitol, bases recognized for use as vehicles fall into four general and mannitol often are included because they can act classes: hydrocarbon bases, absorption bases, water-re- as filler and binder as well as serve as sweetening agents. movable bases, and water-soluble bases. Approved FD&C and D&C dyes or lakes (dyes adsorbed Hydrocarbon Bases—Also known as oleaginous onto insoluble aluminum hydroxide) also may be pre- ointment bases, they allow the incorporation of only sent. small amounts of an aqueous component. Ointments The manufacturing of compressed lozenges is essen- prepared from hydrocarbon bases act as occlusive dress- tially the same as that for conventional tableting, with ings and provide prolonged contact of the API with the the exception that a tablet press capable of making lar- skin. They are difficult to remove and do not change ger tablets and exerting greater force to produce harder physical characteristics upon aging. tablets may be required (see Tablets). Absorption Bases—Allow the incorporation of aque- The paste used to produce lozenges manufactured by ous solutions. Such bases include only anhydrous com- stamping or cutting contains a moistening agent, su- ponents (e.g., Hydrophilic Petrolatum)orwater-in-oil crose, and flavoring and sweetening agents. The homog- emulsions (e.g., Lanolin). Absorption bases are also useful enous paste is spread as a bed of uniform thickness, and as emollients. the lozenges are cut or stamped from the bed and are Water-Removable Bases—Oil-in-water emulsions allowed to dry. Some lozenges are prepared by forcing (e.g., Hydrophilic Ointment) and are sometimes referred dampened powders under low pressure into mold cavi- to as creams (see Emulsions). They may be readily washed ties and then ejecting them onto suitable trays for drying from the skin or clothing with water, making them ac- at moderate temperatures. ceptable for cosmetic reasons. Other advantages of the water-removable bases are that they can be diluted with water and that they favor the absorption of serous dis- charges in dermatological conditions. In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1291

ly used as a base for ophthalmic drugs. Some absorption Water-Soluble Bases—Also known as greaseless bases, water-removable bases, and water-soluble bases ointment bases, they are formulated entirely from may be desirable for water-soluble APIs if the bases are water-soluble constituents. Polyethylene Glycol Ointment nonirritating. is the only official preparation in this group. They offer many of the advantages of the water-removable bases and, in addition, contain no water-insoluble substances MANUFACTURE such as petrolatum, anhydrous lanolin, or waxes. They Ointments typically are prepared by either direct incor- are more correctly categorized as gels (see Gels). poration into a previously prepared ointment base or by The choice of an ointment base depends on the action fusion (heating during the preparation of the ointment). desired, the characteristics of the incorporated API, and A levigating agent is often added to facilitate the incor- the latter’s bioavailability if systemic action is desired. The poration of the medicament into the ointment base by product’s stability may require the use of a base that is the direct incorporation procedure. In the fusion meth- less than ideal in meeting other quality attributes. APIs od, the ingredients are heated, often in the range of thathydrolyzerapidly,forexample,aremorestablein 608 to 808. Homogenization is often necessary. The rate hydrocarbon bases than in bases that contain water. of cooling is an important manufacturing detail because Ophthalmic ointments are intended for application di- rapid cooling can impart increased structure to the pro- rectly to the eye or eye-associated structures such as the duct of the fusion method. subconjunctival sac. They are manufactured from steri- lized ingredients under aseptic conditions and meet the requirements under Sterility Tests h71i. Ingredients meet- PACKAGING AND STORAGE ing the requirements described under Sterility Tests h71i Protect from moisture. For emulsified systems, temper- are used if they are not suitable for sterilization proce- ature extremes can lead to physical instability of the dures. Ophthalmic ointments in multiple-dose con- preparation. When this is the case products should be tainers contain suitable antimicrobial agents to control clearly labeled to specify appropriate storage conditions. microorganisms that might be introduced during use un- Ointments typically are packaged either in ointment jars less otherwise directed in the individual monograph or or ointment tubes. Ointment jars are often used for more unless the formula itself is bacteriostatic (see Ophthalmic viscous ointments that do not require sterility. Ointment Ointments h771i, Added Substances). The finished oint- tubes typically are used for less viscous ointments and ment is free from large particles and must meet the re- those such as ophthalmic ointments that require the quirements for Leakage and for Metal Particles under maintenance of sterility. The package sizes for ophthal- Ophthalmic Ointments h771i. The immediate container mic preparations are controlled to minimize the likeli- for ophthalmic ointments is sterile at the time of filling hood of contamination and loss of sterility. and closing. The immediate containers for ophthalmic ointments are sealed and made tamper-proof so that ste- nPoesRevision In-Process rility is ensured at time of first use. A suitable ophthalmic ointment base is nonirritating to the eye and permits diffusion of the API throughout the secretions bathing the eye. Petrolatum is most common-

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1292 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

Pastes Transdermal Systems (Patches)

Pastes are semisolid preparations of stiff consistency Transdermal drug delivery systems (TDSs) are discrete and contain a high percentage of finely dispersed solids. dosage forms that are designed to deliver the API(s) Pastes are intended for application to the skin, oral cavity, through intact skin to the systemic circulation. Typically, or mucous membranes. In veterinary practice, pastes are a TDS is composed of an outer covering (barrier), a drug used for systemic delivery of APIs. reservoir (possibly covered with a rate-controlling Pastes ordinarily do not flow at body temperature and membrane), a contact adhesive applied to some or all thus can serve as occlusive, protective coatings. As a con- parts of the system (to attach the TDS to the skin sur- sequence, pastes are more often used for protective ac- face), and a protective layer that is removed before the tion than are ointments. patch is applied. The activity of a TDS is defined in terms Fatty pastes that have a high proportion of hydrophilic of the release rate of the API(s) from the system. The total solids appear less greasy and more absorptive than oint- duration of drug release from the system and the system ments. They are used to absorb serous secretions and are surface area also may be stated. often preferred for acute lesions that have a tendency to- Most TDSs can be considered either matrix-type or ward crusting, vesiculation, or oozing. reservoir-type systems. Matrix-type patches are often fur- Dental pastes may be applied to the teeth, or alterna- ther divided into monolithic adhesive matrix or polymer tively they may be indicated for adhesion to the mucous matrix types. Reservoir-type systems include liquid reser- membrane for a local effect (e.g., Triamcinolone Acetonide voir systems and solid-state reservoir systems. Solid-state Dental Paste). Some paste preparations intended for ani- reservoir patches also include multilaminate adhesive mals are administered orally. The paste is squeezed into and multilaminate polymer matrix systems. the mouth of the animal, generally at the back of the Drug delivery from some TDSs is controlled by diffu- tongue, or is spread inside the mouth. sion kinetics. The API diffuses from the drug reservoir di- rectly or through the rate-controlling membrane and/or contact adhesive and then through the skin into the gen- PREPARATION eral circulation. Modified-release systems are generally Pastes can be prepared by direct incorporation or by designed to provide drug delivery at a constant rate so fusion (the use of heat to soften the base). The solid in- that a true steady-state blood concentration is achieved gredients often are incorporated following comminution and maintained until the system is removed. Other TDSs and sieving. If a levigating agent is needed, a portion of work by active transport of the API. For example, ionto- the ointment base is often employed rather than a liquid. phoretic transdermal delivery uses the current between two electrodes to enhance the movement of ionized APIs through the skin. LABELING AND STORAGE TDSs are applied to the body areas recommended by Veterinary products should be labeled to ensure they the labeling. The API content of the system provides a are not administered to humans. Labeling should indi- reservoir that, by design, maintains a constant API con- cate the need for protection from heat. centration at the system-skin interface. The dosing inter- val of the system is a function of the amount of API in the reservoir and the release rate. Some API concentration In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1293 may remain in the reservoir at the end of the dosing in- Pellets terval, in particular for diffusion-controlled delivery Pellets are dosage forms composed of small, solid par- mechanisms. [NOTE—Where the API is intended for local ticles of uniform shape sometimes called beads. Typically, action, it may be embedded in adhesive on a cloth or pellets are nearly spherical but this is not required. Pellets plastic backing. This type of product is more correctly may be administered by the oral (gastrointestinal) or by called a plaster or tape (see Plasters and Tapes).] the injection route (see also Implants). Pellet formulations may provide several advantages including physical sepa-

PREPARATION ration for chemically or physically incompatible mate- rials, extended release of the API, or delayed release to TDSs require a backing, a means of storing the API for protect an acid-labile API from degradation in the stom- delivery to the skin, an adhesive to attach the system to ach or to protect stomach tissues from irritation. Extend- the skin, and a removable release liner to protect the ad- ed-release pellet formulations may be designed with the hesive, API, and excipients before application. The back- API dispersed in a matrix, or the pellet may be coated ing has low moisture- and vapor-transmission rates to with an appropriate polymer coating that modifies the support product stability. The adhesive layer may contain drug-release characteristics. Alternatively, the pellet de- the API and permeation enhancers in the case of matrix- sign may combine these two approaches. In the case of type systems or multi-laminate reservoir systems for delayed-release formulations, the coating polymer is which a priming dose is desired. Adhesive may be ap- chosen to resist dissolution at the lower pH of the gastric plied to the entire patch release surface or merely to environment but to dissolve in the higher pH intestinal the periphery. Liquid reservoir systems are often environment. Injected or surgically administered pellet formed–filled–sealed between the backing and release- preparations (see Implants) are often used to provide controlling materials. For monolithic adhesive matrix sys- continuous therapy for periods of months or years. tems, the API and excipients are applied as a solution or Pellet dosage forms may be designed as single or mul- suspension either to the backing or the release liner, and tiple entities. Often implanted pellets will contain the de- the solvent is allowed to evaporate. sired API content in one or several units. In veterinary practice, 4 to 8 pellets may be implanted in the for

PACKAGING AND STORAGE cattle, depending on animal size. Oral pellets typically are contained within hard gelatin capsules for administra- Storage conditions are clearly specified because ex- tion. Although there are no absolute requirements for treme temperature excursions can influence the perfor- size, the useful size range of pellets is governed by the mance of some systems. practical constraints of the volume of commonly used capsules and the need to include sufficient numbers of LABELING pellets in each dose to ensure uniform dosing of the API. As a result, many pellets used for oral administration

The labeling should clearly indicate any performance Revision In-Process fall within a size range of 8 to 24 mesh. Pellet formula- limitations of the system (e.g., influence of application tions sometimes are used to minimize variability associat- site, hydration state, hair, or other variables). ed with larger dosage forms caused by gastric retention upon stomach emptying.

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PACKAGING AND STORAGE Enteric-coated (delayed-release) pellet formulations and some extended-release formulations are prepared Pellets for oral administration generally are filled into by applying a coating to the formulated particles. The hard gelatin capsules and are placed in bottles or blister coating must be applied as a continuous film over the en- packages. The packaging provides suitable protection tire surface of each particle. Because a small population from moisture to ensure the stability of the pellet formu- of imperfectly coated particles may be unavoidable, oral lation as well as to preserve desirable moisture content of pellets are designed to require the administration of a the capsule shells. Pellets for implantation are sterile and large number in a single dose to minimize any adverse should be packaged in tight containers suitable for main- influence of imperfectly coated pellets on drug delivery. taining sterile contents. Pellets may be stored under con- trolled room temperature conditions unless other conditions are specifically noted. PREPARATION

The desired performance characteristics determine the LABELING AND USE manufacturing method chosen. In general, pellet dosage forms are manufactured by wet extrusion processes fol- Pellets for oral administration that are formulated to lowed by spheronization, by wet or dry coating proces- provide delayed or controlled release must be swallowed ses, or by compression. Manufacture of pellets by wet intact to ensure preservation of the desired release char- coating usually involves the application of successive acteristics. These products should be labeled accordingly coatings upon nonpareil seeds. This manufacturing pro- to ensure that the material is not crushed or chewed dur- cess frequently is conducted in fluid-bed processing ing administration. equipment. Dry powder coating or layering processes of- ten are performed in specialized rotor granulation equip- Pills ment. The extent of particle growth achievable in wet Pills are API-containing small round solid bodies in- coating processes is generally more limited than the tended for oral administration. At one time pills were growth that can be obtained with dry powder layering the most extensively used oral dosage form, but they techniques, but either method allows the formulator to have been replaced by compressed tablets and capsules. develop and apply multiple layers of coatings to achieve Pills are distinguished from tablets because pills are man- the desired release profile. The manufacture of pellets by ufactured by a wet massing and molding technique, compression is largely restricted to the production of ma- while tablets are formed by compression. terial for subcutaneous implantation. This method of manufacture provides the necessary control to ensure dose uniformity and generally is better suited to aseptic PREPARATION processing requirements. Excipients are selected on the basis of their ability to Alternatively, microencapsulation techniques can be produce a mass that is firm and plastic. The API is triturat- used to manufacture pellets. Coacervation coating tech- ed with powdered excipients in serial dilutions to attain a niques typically produce coated particles that are much uniform mixture. Liquid excipients that act to bind and smaller than those made by other techniques. provide plasticity to the mass are subsequently added In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1295 to the dry materials. The mass is formed by kneading. PACKAGING AND STORAGE The properties of firmness and plasticity are necessary Plasters are preserved in well-closed containers, prefer- to permit the mass to be worked and retain the shape ably at controlled room temperature. produced. Cylindrical pill pipes are produced from por- tions of the mass. The pill pipe is cut into individual Powders lengths corresponding to the intended pill size, and the pills are rolled to form the final shape. Pill-making ma- Powders are defined as a solid or a mixture of solids in a chines can automate the preparation of the mass, pro- finely divided state intended for internal or external use. duction of pill piping, and the cutting and rolling of pills. Powders used as pharmaceutical dosage forms may con- tain one or more APIs and can be mixed with water for oral administration or injection. Often pediatric antibiot- ics utilize a powder dosage form for improved stability. In Labeling and use instructions for pills are similar to some areas medicated powders are used for extempora- those for tablets. Although many pills are resistant to neous compounding of preparations for simultaneous breakage, some pills are friable. Appropriate handling administration of multiple APIs. Medicated powders also guidelines should be provided in such cases in order to can be inhaled for pulmonary administration (see Dry avoid breakage. Powder Inhalers). Aerosolized powders for the lungs typ- ically contain processing aids to improve flow and ensure Plasters uniformity (see Aerosols, Nasal Sprays, Metered-Dose In- halers, and Dry Powder Inhalers h601i). Powders can also A plaster is a semisolid substance for external applica- be used topically as a dusting powder. tion and usually is supplied on a support material. Plasters Externally applied powders should have a particle size are applied for prolonged periods to provide protection, of 150 mm or less (typically in the 50- to 100-mm range) in support, or occlusion (maceration). order to prevent a gritty feel on the skin that could fur- Plasters consist of an adhesive layer that may contain ther irritate traumatized skin. Powders are grouped ac- active substances. This layer is spread uniformly on an ap- cording to the following terms: very coarse, coarse, propriate support that is usually made of a rubber base or moderately coarse, fine, and very fine (see Powder Fine- synthetic resin. Unmedicated plasters are designed to ness h811i). The performance of powder dosage forms provide protection or mechanical support to the site of can be affected by the physical characteristics of the application. These plasters are neither irritating nor sen- powder. Particle size can influence the dissolution rate sitizing to the skin. of the particles and affect bioavailability. For dispersed Plasters are available in a range of sizes or cut to size to delivery systems, particle size can influence the mixing effectively provide prolonged contact to the site of appli- and segregation behavior of the particle, which in turn cation. They adhere firmly to the skin but can be peeled affects the uniformity of the dosage form. off the skin without causing injury. nPoesRevision In-Process One example of a plaster currently in use is plasters used for the removal of corns by the keratolytic action of salicylic acid.

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PREPARATION vidual folded papers. Hygroscopic powders pose special challenges and typically are dispensed in moisture- Powder dosage forms can be produced by the combi- resistant packaging. nation of multiple components into a uniform blend. This can also involve particle size reduction, a process re-

ferred to as comminution. Mills and pulverizers are used LABELING to reduce the particle size of powders when necessary. As Typical warning statements include: the particle size is decreased, the number of particles and External powders must indicate: ‘‘External Use the surface area increase, which can increase the dissolu- Only’’. tion rate and bioavailability of the API. Oral powders should indicate: ‘‘For Oral Use Only’’. Blending techniques for powders include those used in Powders intended for veterinary use must indicate: compounding pharmacy such as spatulation and tritura- ‘‘For Veterinary Use Only’’. tion (see Pharmaceutical Compounding Nonsterile Prepara- Individual monographs specify the labeling require- tions h795i). Industrial processes may employ sifting or ments for powder dosage forms that are listed in USP– tumbling the powders in a rotating container. One of NF. Oral powders for reconstitution prior to dispensing the most common tumble blenders is a V-blender, which typically have a limited shelf life (for example, 2 weeks), is available in a variety of scales suitable for small-scale and the dispensed product should indicate a beyond-use and large-scale compounding and industrial production. date based on the date of the water addition. Pharma- Powder flow can be influenced by both particle size ceutical powders that are compounded indicate a be- and shape. Larger particles generally flow more freely yond-use date. Compounded preparations typically are than do fine particles. Powder flow is an important attri- intended for immediate use and have short-term storage bute that can affect the packaging or dispensing of a durations. medicated powder.

Medicated Soaps And

PACKAGING AND STORAGE Medicated soaps and shampoos are solid or liquid pre- Powders for pharmaceutical use can be packaged in parations intended for topical application to the skin or multiple- or single-unit containers. Bulk containers have scalp followed by subsequent rinsing with water. Soaps been used for antacid powders and for laxative powders. and shampoos are emulsions or surface-active composi- In these instances the patient dissolves the directed tions that readily form emulsions or foams upon the ad- amount in water prior to administration. This type of dition of water followed by rubbing. Incorporation of multiple-unit packaging is acceptable for many APIs but APIs in soaps and shampoos combines the cleansing/ should not be utilized for powders that require exact dos- degreasing abilities of the vehicle and facilitates the top- ing. Multiple-unit powders for topical application often ical application of the API to affected areas, even large ar- are packaged in a container with a sifter top. eas, of the body. The surface-active properties of the Potent APIs in a powder dosage form are dispensed in vehicle facilitate contact of the API with the skin or scalp. unit-of-use allocations in folded papers, cellophane en- Medicated and formulations frequently velopes, or packets. Powder boxes are often used by contain suitable antimicrobial agents to protect against the dispensing pharmacist to hold multiple doses of indi- bacteria, yeast, and mold contamination. In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1297

PREPARATION Substances in solutions are more susceptible to chem- ical instability than they are in the solid state and dose- The preparation of medicated soaps and shampoos fol- for-dose generally are heavier and more bulky than solid lows techniques frequently used for the preparation of dosage forms. These factors increase the cost of packag- emulsified systems. To ensure uniformity, the API(s) must ing and shipping relative to that of solid dosage forms. be added to the vehicle prior to congealing (in the case Solution dosage forms can be administered by injection; of soaps) followed by thorough mixing. If the medication inhalation; and the mucosal, topical/dermal, and gastro- is present as a suspension, the particle size must be con- intestinal routes. Terminology for solutions in veterinary trolled to promote uniform distribution of the API and practice includes spot-ons or pour-ons that refer to solu- possibly optimize performance. Because soap manufac- tions that are applied to an animal’s skin for systemic ab- ture frequently involves processing the ingredients at el- sorption, dips that refer to solutions that are used for evated temperature, care must be exercised to avoid washing and disinfection (e.g., udders, eggs, and whole excessive degradation of the API during processing. animals), and drenches that include solutions that are orally administered to livestock, usually with a dosing de- PACKAGING AND STORAGE vice. Solutions administered by injection are officially ti- tled injections (see Injections h1i). Individual monographs specify the packaging and Solutions intended for oral (gastrointestinal) adminis- storage requirements for medicated soaps and sham- tration usually contain flavorings and colorants to make poos in USP–NF. the medication more attractive and palatable for the pa- tient or consumer. When needed, they also may contain LABELING AND USE stabilizers to maintain chemical and physical stability and preservatives to prevent microbial growth. Medicated soaps and shampoos are clearly labeled to indicate ‘‘For External Use Only’’. The preparations also clearly advise the patient to discontinue use and consult STORAGE AND USE a physician/veterinarian if skin irritation or inflammation Light-resistant containers should be considered when occurs or persists following application. photolytic chemical degradation is a potential issue. To prevent water or solvent loss, solutions are stored in tight Solutions containers. Instructions to ensure proper dosing and ad- A solution is a liquid preparation that contains one or ministration must accompany the product more dissolved chemical substances in a suitable solvent or mixture of mutually miscible solvents. Because mole- Sprays (Nasal, Pulmonary, or Solutions For cules of a drug substance in solution are uniformly dis- Nebulization) persed, the use of solutions as dosage forms generally A spray is a preparation that contains a therapeutic provides assurance of uniform dosage upon administra- nPoesRevision In-Process agent(s) in either the liquid or solid state and is intended tion and good accuracy when the solution is diluted or for administration as a fine mist of small aqueous drop- otherwise mixed. lets. The droplets may be generated by means other than the use of a volatile propellant (see Aerosols). The mech-

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anism for droplet generation and the intended use of the nipulation of the package by the patient. This generally preparation distinguish the various classes of sprays. A involves squeezing the sides of the container and expel- spray is composed of a pump, container, valve, actuator, ling the formulation through the nozzle of the container. and nozzle in addition to the formulation containing the Finally, liquid sprays may be generated from solutions drug(s), solvents, and excipients. Each component plays by nebulization. This is a method for continuous genera- a role in determining the critical characteristics of the tion of a fine mist of aqueous droplets from a drug-con- mist of fine droplets. Droplet size and size distribution, taining solution by application of the Venturi principle, uniformity of delivery of dose, plume geometry, and ultrasonic energy, or other suitable mechanical means. droplet velocity are critical parameters that influence The generated mist is directed to the patient for inhala- the efficiency of drug delivery. When the preparation is tion, sometimes with the aid of an appropriate tube or supplied as a multi-dose container, the addition of a suit- face mask. Although formulations for nebulization typi- able antimicrobial preservative may be necessary. cally are solutions, they also may be fine suspensions or Spray formulations intended for nasal or pulmonary emulsions. administration have an aqueous base. Nasal preparations may be solutions, suspensions, or emulsions intended for PACKAGING local or systemic effect. Nasal delivery may be employed for drugs with high hepatic extraction ratios. Pulmonary Containers typically are made of a rigid plastic, but preparations typically are solutions, although appropri- metal or glass may be suitable. ately sized suspension formulations are permissible. Pre- The pump is designed to allow convenient parations are usually isotonic and may contain excipients one-handed operation. The nasal spray nozzle is de- to control pH and viscosity. signed so that it fits comfortably into the vestibule of Metered-dose sprays typically require manually de- the nasal cavity and allows the plume to be directed to- pressing the top of the container to activate a metered ward the appropriate region of the cavity. valve system. Depending on the design of the formula- tion and the valve system, the droplets generated may LABELING AND USE be intended for immediate inhalation through the mouth and deposition in the pulmonary tree or for inha- Typical warning statements include: lation into the nose and deposition in the nasal cavity. All inhalation sprays should indicate: ‘‘For Inhalation These preparations are commonly known as metered- Administration Only. Keep out of the reach of chil- dose sprays. The design of the pump, container, valve, dren unless otherwise prescribed. Avoid spraying in- actuator, nozzle, and formulation are critical to the per- to the eyes.’’ formance of the product. All nasal sprays indicate: ‘‘For Intranasal Administra- Alternatively, sprays can be generated by package de- tion Only’’. signs that do not accurately control the volume of formu- The device should contain a statement that patients lation delivered. These presentations release the should seek advice and instruction from a health care formulation as a fine mist of droplets upon physical ma- professional about the proper use of the device. Guid- In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1299 ance should be provided about the proper care and cool in molds. A suitable quantity of hardening agents cleaning of the device to prevent introduction of mi- may be added to counteract the tendency of some APIs crobes into the pulmonary airways. (such as and phenol) to soften the base. The finished suppository melts at body temperature. Suppositories A variety of vegetable oils, such as coconut or palm ker- nel, modified by esterification, hydrogenation, or frac- Suppositories are dosage forms adapted for applica- tionation, are used as cocoa butter substitutes to tion into the rectum. They usually melt, soften, or dis- obtain products that display varying compositions and solve at body temperature. A suppository may have a melting temperatures (e.g., Hydrogenated Vegetable Oil local protectant or palliative effect or may deliver an and Hard Fat). These products can be designed to reduce API for systemic or local action. rancidity while incorporating desired characteristics such Suppository bases typically include cocoa butter, gly- as narrow intervals between melting and solidification cerinated gelatin, hydrogenated vegetable oils, mixtures temperatures and melting ranges to accommodate for- of polyethylene glycols of various molecular weights, and mulation and climatic conditions. fatty acid esters of polyethylene glycol. The suppository APIs can be incorporated into glycerinated gelatin ba- base can have a notable influence on the release of the ses by addition of the prescribed quantities to a vehicle API(s). Although cocoa butter melts quickly at body tem- consisting of about 70 parts of glycerin, 20 parts of gel- perature, it is immiscible with body fluids and this inhibits atin, and 10 parts of water. the diffusion of fat-soluble APIs to the affected sites. Poly- Several combinations of polyethylene glycols that have ethylene glycol is a suitable base for some antiseptics. In melting temperatures that are above body temperature cases when systemic action is desired, incorporating the are used as suppository bases. Because release from these ionized rather than the non-ionized form of the API may bases depends on dissolutionratherthanonmelting, help maximize bioavailability. Although non-ionized APIs there are significantly fewer problems in preparation partition more readily out of water-miscible bases such as and storage than is the case for melting-type vehicles. glycerinated gelatin and polyethylene glycol, the bases However, high concentrations of higher molecular themselves tend to dissolve very slowly, which slows weight polyethylene glycols may lengthen dissolution API release. Cocoa butter and its substitutes (e.g, Hard time, resulting in problems with retention. Fat) perform better than other bases for allaying irritation Several non-ionic surface-active agents closely related in preparations intended for treating internal hemor- chemically to the polyethylene glycols can be used as rhoids. Suppositories for adults are tapered at one or suppository vehicles. Examples include polyoxyethylene both ends and usually weigh about 2 g each. sorbitan fatty acid esters and the polyoxyethylene stea- rates. These surfactants are used alone or in combination PREPARATION with other suppository vehicles to yield a wide range of melting temperatures and consistencies. A notable ad- Cocoa butter suppositories have cocoa butter as the

vantage of such vehicles is their water dispersibility. How- Revision In-Process base and can be made by incorporating the finely divid- ever, care must be taken with the use of surfactants ed API into the solid oil at room temperature and suitably shaping the resulting mass or by working with the oil in the melted state and allowing the resulting suspension to

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because they may either increase the rate of API absorp- Suspensions tion or interact with the API to reduce therapeutic activ- A suspension is a biphasic preparation consisting of sol- ity. id particles dispersed throughout a liquid phase. Suspen- Compounding suppositories using a suppository base sion dosage forms may be formulated for specific routes typically involves melting the suppository base and disso- of administration such as oral suspensions, topical sus- lution or dispersion of the API in the molten base (see pensions, or suspensions for aerosols (see Aerosols). Some Pharmaceutical Compounding—Nonsterile Preparations suspensions are prepared and ready for use, and others h795i). When compounding suppositories, the manufac- are prepared as solid mixtures intended for reconstitu- turer or compounding professional prepares an excess tion with an appropriate vehicle just before use. The term amount of total formulation to allow the prescribed ‘‘milk’’ is sometimes used for suspensions in aqueous ve- quantity to be accurately dispensed. In compounding hicles intended for oral administration (e.g., Milk of Mag- suppositories, avoid caustic or irritating ingredients, care- nesia). The term ‘‘magma’’ is often used to describe fully select a base that will allow the API to provide the suspensions of inorganic solids, such as clays in water, intended effect, and in order to minimize abrasion of that display a tendency toward strong hydration and ag- the rectal membranes, reduce solid ingredients to the gregation of the solid, giving rise to gel-like consistency smallest reasonable particle size. A representative num- and thixotropic rheological behavior (e.g., Bentonite ber of the compounded suppositories should be Magma). The term ‘‘lotion’’ may refer to a suspension weighed to confirm that none is less than 90% or more dosage although the liquid phase in these preparations than 110% of the average weight of all units in the batch. is commonly an emulsion intended for application to the skin (e.g., Calamine Topical Suspension;seeEmul-

STORAGE AND USE sions). Some suspensions are prepared in sterile form and are used as injectables (see Injections h1i). Other ster- Suppositories typically are provided in unit-dose pack- ile suspensions are for ophthalmic or otic administration. aging with storage instructions to prevent melting of the Suspensions generally are not injected intravenously, epi- suppository base. Suppositories with cocoa butter base durally, or intrathecally unless the product labeling clear- require storage in well-closed containers, preferably at ly specifies these routes of administration. a temperature below 308(controlled room temperature). Limited aqueous solubility of the API(s) is the most Glycerinated gelatin suppositories require storage in common rationale for developing a suspension. Other tight containers, preferably at a temperature below 28. potential advantages of a suspension include taste mask- Although polyethylene glycol suppositories can be ing and improved patient compliance because of the stored without refrigeration, they should be packaged more convenient dosage form. When compared to solu- in tightly closed containers. tions, suspensions have improved chemical stability. Ide- Include instructions about insertion procedures to en- ally, a suspension should contain small uniform particles sure ease of use and absorption. Labels on polyethylene that are readily suspended and easily re-dispersed follow- glycol suppositories should contain directions that they ing settling. Unless the dispersed solid is colloidal, the be moistened with water before insertion. particulate matter in a suspension likely will settle to the bottom of the container upon standing. Such sedi- mentation may lead to caking and solidification of the In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1301 sediment and difficulty in re-dispersing the suspension the range of 5 mm or smaller. The rationale for the devel- upon agitation. To prevent such problems, manufactur- opment of injectable suspensions includes poor API solu- ers commonly add ingredients to increase viscosity and bility, improved chemical stability, prolonged duration of the gel state of the suspension or flocculation, including action, and avoidance of first-pass . Care is clays, surfactants, polyols, polymers, or sugars. Frequent- needed in selecting the sterilization technique because ly, thixotropic vehicles are employed to counter particle- it may affect product stability or alter the physical proper- settling tendencies, but these vehicles must not interfere ties of the material. with pouring or re-dispersal. Additionally, the density of the dispersed phase and continuous phase may be mod- PREPARATION ified to further control settling rate. For topical suspen- sions, rapid drying upon application is desirable. Suspensions are prepared by adding suspending The product is both chemically and physically stable agents or other excipients and purified water or oil to sol- throughout its shelf life. Temperature can influence the id APIs and mixing to achieve uniformity. In the prepara- viscosity (and thus suspension properties and the ease tion of a suspension, the characteristics of both the of removing the dose from the bottle), and temperature dispersed phase and the dispersion medium should be cycling can lead to changes in the particle size of the dis- considered. During development manufacturers should persed phase via . When manufacturers define an appropriate particle size distribution for the conduct stability studies to establish product shelf life suspended material to minimize the likelihood of particle and storage conditions, they should cycle conditions size changes during storage. (freeze/thaw) to investigate temperature effects. In some instances the dispersed phase has an affinity All suspensions contain suitable antimicrobial agents to for the vehicle and is readily wetted upon its addition. protect against bacterial, yeast, and mold contamination For some materials the displacement of air from the solid (see Antimicrobial Effectiveness Testing h51i). surface is difficult, and the solid particles may clump to- Suspensions for reconstitution are dry powder or gran- gether or float on top of the vehicle. In the latter case, a ular mixtures that require the addition of water or a sup- wetting agent is used to facilitate displacement of air plied formulated diluent before administration. This from the powder surface. Surfactants, alcohol, glycerin, formulation approach is frequently used when the chem- and other hydrophilic liquids can be employed as wet- ical or physical stability of the API or suspension does not ting agents when an aqueous vehicle will be used as allow sufficient shelf life for a preformulated suspension. the dispersion phase. These agents function by displac- Typically, these suspensions are refrigerated after recon- ing the air in the crevices of the particles and dispersing stitution to increase their shelf life. For this type of sus- the particles. In the large-scale preparation of suspen- pension, the powder blend is uniform and the powder sions, wetting of the dispersed phase may be aided by readily disperses when reconstituted. Taste of the recon- the use of high-energy mixing equipment such as stituted suspension is also an important attribute because mills or other rotor–stator mixing devices. many suspensions are used for pediatric populations. After the powder has been wetted, the dispersion me- Revision In-Process Injectable suspensions generally are intended for either dium (containing the soluble formulation components subcutaneous or intramuscular routes of administration such as colorants, flavorings, and preservatives) is added and should have a controlled particle size, typically in in portions to the powder, and the mixture is thoroughly

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blended before subsequent additions of the vehicle. A perature for the product because temperature can portion of the vehicle is used to wash the mixing equip- influence the viscosity and density (that affect suspension ment free of suspended material, and this portion is used properties and the ease of removal of the dose from the to bring the suspension to final volume and ensure that bottle), and temperature cycling can lead to changes in the suspension contains the desired concentration of sol- particle size of the dispersed phase. Suspensions require id matter. The final product may be passed through a col- storage in tight containers. Avoid freezing. loid mill or other blender or mixing device to ensure uniformity. When appropriate, preservatives are included LABELING AND USE in the formulation of suspensions to protect against bac- terial and mold contamination. Instructions to ensure proper dosing and administra- Suspensions are shaken before the dose is dispensed. tion must accompany the product. When labeling a sus- Because of the viscosity of many suspension vehicles, pension, consider any air that might be entrained in the air entrainment may occur during dosing. The formula- preparation as a result of shaking, and avoid such en- tion process allows evaluation of this possibility; adjust- trainment. Compounded suspensions should indicate a ments in vehicle viscosity or the incorporation of low beyond-use date that is calculated from the time of com- levels of antifoaming agents are common approaches pounding. Suspensions are shaken well before use to en- to minimize air entrainment. Alternatively, specific in- sure uniform distribution of the solid in the vehicles. structions for shaking the formulation may be provided to minimize air incorporation and ensure accurate dos- Tablets ing. Tablets are solid dosage forms in which the API is blended with excipients and compressed into the final

PACKAGING AND STORAGE dosage. Tablets are the most widely used dosage form in the U.S. Tablet presses use steel punches and dies to Individual monographs specify the packaging and prepare compacted tablets by the application of high storage requirements for suspension products. Typically, pressures to powder blends or granulations. Tablets can the monograph will indicate a container type such as be produced in a wide variety of sizes, shapes, and sur- tight, well-closed, or light-resistant and may indicate face markings. Capsule-shaped tablets are commonly re- storage conditions such as controlled room temperature. ferred to as caplets. Specialized tablet presses may be For additional information about meeting packaging re- used to produce tablets with multiple layers or with spe- quirements listed in the individual monographs, refer to cially formulated core tablets placed in the interior of the Containers—Glass h660i, Containers—Plastic h661i, Con- final dosage form. These specialized tablet presentations tainers—Performance Testing h671i, Good Packaging Prac- can delay or extend the release of the API(s) or physically tices h1177i,andtheGeneral Notices for statements separate incompatible APIs. Tablets may be coated by a about preservation, packaging, storage, and labeling. variety of techniques to provide taste masking, protec- Acceptable suspension of the particulate phase de- tion of photo-labile API(s), prolonged or delayed release, pends on the particle size of the dispersed phase as well or unique appearance (colors). When no deliberate effort as the viscosity and density of the vehicle. Clear instruc- has been made to modify the API release rate, tablets are tion is provided regarding the appropriate storage tem- referred to as immediate-release. In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1303

Tablet Triturates—Small, usually cylindrical, molded enhancers like brewers yeast or /fish-based flavors. or compacted tablets. Tablet triturates traditionally were Soft chewable tablets are made by a molding or extru- used as dispensing tablets in order to provide a conve- sion process, frequently with more than 10% water to nient, measured quantity of a potent API for compound- help maintain a pliable, soft product. ing purposes, but they are rarely used today. Orally Disintegrating Tablets—Intended to disin- Hypodermic Tablets—Molded tablets made from tegrate rapidly within the mouth to provide a fine disper- completely and readily water-soluble ingredients; for- sion before the patient swallows the resulting merly intended for use in making preparations for hypo- suspension. Some of these dosage forms have been for- dermic injection. They may be administered orally or mulated to facilitate rapid disintegration and are manu- sublingually when rapid API availability is required, as in factured by conventional means or by using the case of Nitroglycerin Sublingual Tablets. lyophilization or molding processes. Tablets—Large, usually elongated, tablets in- Sublingual Tablets—Intended to be inserted be- tended for administration to large animals. Conventional neath the tongue, where the API is absorbed directly tableting processes can be used to manufacture bolus through the oral mucosa. As with buccal tablets, few APIs tablets, but due to their size higher compression forces are extensively absorbed in this way, and much of the API may be necessary. is swallowed and is available for gastrointestinal absorp-

Buccal Tablets—Intended to be inserted in the buc- tion. cal pouch, where the API is absorbed directly through the oral mucosa. Few APIs are readily absorbed in this way PREPARATION (examples are nitroglycerin and certain steroid hor- mones). Most compacted (compressed) tablets consist of the API(s) and a number of excipients. These excipients Effervescent Tablets—Prepared by compaction and may include fillers (diluents), binders, disintegrating contain, in addition to the API(s), mixtures of acids (e.g., agents, lubricants, and glidants. Approved FD&C and citric acid or tartaric acid) and carbonates and/or hydro- D&C dyes or lakes, flavors, and sweetening agents also gen carbonates. Upon contact with water, these formu- may be present. lations release carbon dioxide, producing the Fillers or diluents are added when the quantity of API(s) characteristic effervescent action. is too small or the properties of the API do not allow sat- Hard and Soft Chewable Tablets—Formulated and isfactory compaction in the absence of other ingredients. manufactured to produce a pleasant-tasting residue in Binders impart adhesiveness to the powder blend and the mouth and to facilitate swallowing. Hard chewable promote tablet formation and maintenance of API uni- tablets are prepared by compaction, usually utilizing formity in the tableting mixture. Disintegrating agents mannitol, sorbitol, or sucrose as binders and fillers, and facilitate reduction of the tablet into small particles upon contain colors and flavors to enhance their appearance contact with water or biological fluids. Lubricants reduce and taste. Some chewable tablets may be swallowed friction during the compaction and ejection cycles. Gli- Revision In-Process without compromising delivery of the API. Chewable dants improve powder fluidity, powder handling proper- tablets are clearly labeled to indicate whether chewing is necessary to ensure reliable release of the API(s). Hard chewable tablets in veterinary medicine often have flavor

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ties, and tablet weight control. Colorants are often add- proach. Sugar-coated tablets have considerably thicker ed to tablet formulations for esthetic value or for product coatings that are primarily sucrose with a number of in- identification. organic diluents. A variety of film-coating polymers are Tablets are prepared from formulations that have been available and enable the development of specialized re- processed by one of three general methods: wet granu- lease profiles. These formulations are employed to pro- lation, dry granulation (roll compaction or slugging), tect acid-labile APIs from the acidic stomach and direct compression. environment as well as to prolong the release of the Wet Granulation—Involves the mixing of dry pow- API to reduce dosing frequency (see Dissolution h711i ders with a granulating liquid to form a moist granular or Disintegration h701i). mass that is dried and sized prior to compression. It is particularly useful in achieving uniform blends of low- PACKAGING, STORAGE, AND LABELING dose APIs and facilitating the wetting and dissolution of poorly soluble, hydrophobic APIs. Individual monographs specify the packaging and storage requirements for tablet products. Typically, the Dry Granulations—Can be produced by passing powders between rollers at elevated pressure (roll com- monograph will indicate the container type such as tight, well-closed, or light-resistant. For additional information paction). Alternatively, dry granulation also can be car- on meeting USP packaging requirements see ried out by the compaction of powders at high pressures on tablet presses, a process also known as slug- Containers—Glass h660i,Containers—Plastic h661i and Containers—Performance Testing h671i. Effervescent tab- ging. In either case the compacts are sized before com- lets are stored in tightly closed containers or moisture- pression. Dry granulation improves the flow and handling properties of the powder formulation without proof packs and are labeled to indicate that they should not be swallowed directly. involving moisture in the processing. Direct Compression—Tablet processing involves dry Tapes blending of the API(s) and excipients followed by com- pression. The simplest manufacturing technique, direct A tape is a dosage form suitable for delivering APIs to compression is acceptable only when the API and excip- the skin. It consists of an API(s) impregnated into a dura- ients possess acceptable flow and compression proper- ble yet flexible woven fabric or extruded synthetic mate- ties without prior process steps. rial that is coated with an adhesive agent. Typically the Tablets may be coated to protect the ingredients from impregnated API is present in the dry state. The adhesive air, moisture, or light; to mask unpleasant tastes and layer is designed to hold the tape securely in place with- odors; to improve tablet appearance; and to reduce dust- out the aid of additional bandaging. Unlike transdermal iness. In addition, coating may be used to protect the API patches, tapes are not designed to control the release from acidic pH values associated with gastric fluids or to rate of the API. control the rate of drug release in the gastrointestinal The API content of tapes is expressed as amount per tract. surfaceareawithrespecttothetapesurfaceexposed The most common coating in use today is a thin film to the skin. The use of an occlusive dressing with the tape coating composed of a polymer that is derived from cel- lulose. Sugar coating is an alternative, less common ap- In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1305 enhances the rate and extent of delivery of the API to AROMATIC WATER (NOT PREFERRED; see Solution): A clear, deeper layers of the skin and may result in greater sys- saturated, aqueous solution of volatile oils or other temic absorption of the API. aromatic or volatile substances.

AURAL (Auricular) (NOT PREFERRED; see Otic): For admin- istration into, or by way of, the ear. LABELING, STORAGE, AND USE BEAD (NOT PREFERRED; see Pellets): A solid dosage form Label to indicate ‘‘External Use Only’’. Tapes are stored in the shape of a small sphere. In most products a in tight containers protected from light and moisture. To unit dose consists of multiple beads. employ the tape, one cuts a patch slightly larger than the BLOCKS: A large veterinary product intended to be area that will be treated. The backing paper is removed licked by animals and containing the API(s) and nu- from the adhesive side, and the tape is applied to the trients such as salts, vitamins, and minerals. skin. To ensure optimal adhesion, the tape should not BOLUS (NOT PREFERRED;seeTablet): A large tablet in- be applied to folds in the skin. To minimize systemic ab- tended for administration to large animals. sorption and to ensure good adhesion, tapes should be CAPLET (NOT PREFERRED; see Tablet): Tablet dosage form applied to dry skin. in the shape of a capsule.

CAPSULE: A solid dosage form in which the API, with or GLOSSARY without other ingredients, is filled into either a hard or soft shell. Most capsule shells are composed main- This glossary provides definitions for terms in use in ly of gelatin. medicine and serves as a source of official names for of- CHEWABLE: Attribute of a solid dosage form that is in- ficial articles. Examples of general nomenclature forms tended to be chewed before swallowing. for the more frequently encountered categories of dos- COATED: Attribute of a solid dosage form that is cov- age forms appear in Nomenclature h1121i. In an attempt ered by deposition of an outer solid that is different to be comprehensive, this glossary was compiled without in composition from the core material. the limits imposed by current preferred nomenclature COLLODION (NOT PREFERRED;seeSolution): A prepara- conventions. To clearly identify/distinguish preferred tion that is a solution dosage form composed of pyr- from not preferred terms, entries indicate when a term oxilin dissolved in a solvent mixture of alcohol and is not preferred and direct the user to the current pre- ether and applied externally. ferred term. When a term is described as an attribute of COLLODIAL DISPERSION: A system in which particles of a dosage form, it should not be used in the official name colloidal dimension (i.e., typically between 1 nm for the dosage form. and 1 mm) are distributed uniformly throughout a liquid. AEROSOL: A dosage form consisting of a liquid or solid CONCENTRATE: A liquid or solid preparation of higher preparation packaged under pressure and intended concentration and smaller volume than the final dos- for administration as a fine mist. The descriptive term

age form; usually intended to be diluted prior to ad- Revision In-Process aerosol also refers to the fine mist of small droplets or ministration. The term continues to be used for solid particles that are emitted from the product. veterinary preparations but is being phased out of USP–NF titles for human applications.

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CONVENTIONAL-RELEASE (NOT PREFERRED; see Immediate- ELIXIR (NOT PREFERRED; see Solution): A preparation that Release): Descriptive term for a dosage form in which typically is a clear, flavored, sweetened hydroalco- no deliberate effort has been made to modify the re- holic solution intended for oral use. The term is no lease rate of the API. In the case of capsules and tab- longer used in USP–NF but is commonly encoun- lets, the inclusion or exclusion of a disintegrating tered in compounding pharmacy practice.

agent is not interpreted as a modification. EMOLLIENT: Attribute of a cream or ointment indicat-

CREAM: An emulsion dosage form often containing ing an increase in the moisture content of the skin more than 20% water and volatiles or containing less following application of bland, fatty, or oleaginous than 50% hydrocarbons, waxes, or polyols as the ve- substances.

hicle for the API. Creams are generally intended for EMULSION: A dosage form consisting of a two-phase external application to the skin or mucous mem- system composed of at least two immiscible liquids, branes. one of which is dispersed as droplets (internal or dis-

DELAYED-RELEASE: A type of modified-release dosage persed phase) within the other liquid (external or form. A descriptive term for a dosage form deliber- continuous phase), generally stabilized with one or ately modified to delay release of the API for some more emulsifying agents. Emulsion is not used as a period of time after initial administration. Release of dosage form term if a more specific term is applica- the API is prevented in the gastric environment but ble (e.g., Cream, Lotion,orOintment).

promoted in the intestinal environment; this term ENTERIC-COATED (NOT PREFERRED;seeDelayed-Release): is synonymous with Enteric-Coated or Gastro- Descriptive term for a solid dosage form in which a Resistant. polymer coating has been applied to prevent the re-

DENTAL: Descriptive term for a preparation that is ap- lease of the API in the gastric environment.

plied to the teeth and/or gums for localized action. EXCIPIENT: An ingredient of a dosage form other than

DERMAL: Route of administration to the skin surface. an API.

DOSAGE FORM: A formulation of the API(s) and excipi- EXTENDED-RELEASE: Descriptive term for a dosage form ents in quantities and physical form designed to al- that is deliberately modified to protract the release low the accurate and efficient administration of the rate of the API compared to that observed for an im- API to the human or animal patient. mediate-release dosage form. The term is synony-

DRY POWDER INHALER: A dosage form consisting of a mous with prolonged- or sustained-release. Many mixture of the API(s) and carrier; all components ex- extended-release dosage forms have a pattern of re- ist in a finely divided solid state that is mobilized into lease that begins with a ‘‘burst effect’’ that mimics an a fine mist upon the oral inhalation by the patient. immediate release followed by a slower release of the

EFFERVESCENT: Attribute of an oral dosage form, fre- remaining API in the dosage form.

quently tablets or granules, containing ingredients FEED ADDITIVE: A preparation used in veterinary medi- that, when in contact with water, rapidly release car- cine that is mixed with an animal’s food or water to bon dioxide. The dosage form is dissolved or dis- deliver the API. Three types exist: type A medicated persed in water to initiate the effervescence prior to article, type B medicated feed, and type C medicated ingestion. In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1307

feed. Only type C medicated feed preparations con- shell. Most hard-shell capsules are composed mainly tain the API(s) in concentrations appropriate for ad- of gelatin and are fabricated prior to the filling oper- ministration directly to animals. ation.

FILM: A term used to describe a thin, flexible sheet of IMMEDIATE-RELEASE: Descriptive term for a dosage form material, usually composed of a polymer in an amor- in which no deliberate effort has been made to mod- phous state. Films are applied to solid dosages for ify the API release rate. In the case of capsules and taste masking, product identification, and aesthetic tablets, the inclusion or exclusion of a disintegrating purposes. Films also are employed as a means of oral agent is not interpreted as a modification.

administration of material in a rapidly dissolving IMPLANT: A dosage form that is a solid or semisolid form. material containing the API, that is inserted into the

FOAM: An emulsion dosage form containing dis- body. The insertion process is invasive, and the ma- persed gas bubbles. When dispensed it has a fluffy, terial is intended to reside at the site for a period con- semisolid consistency. sistent with the design release kinetics or profile of

GAS: One of the states of matter having no definite the API(s).

shape or volume and occupying the entire container INHALATION (BY INHALATION): A route of administration when confined. for aerosols characterized by dispersion of the API in-

GASTRO-RESISTANT (NOT PREFERRED; see Delayed-Release): to the airways during inspiration.

Descriptive term for a solid dosage form in which a BY INJECTION: A route of administration of a liquid or polymer coating has been applied to prevent the re- semisolid deposited into a body cavity, fluid, or tissue lease in the gastric environment. by use of a needle.

GEL: A dosage form that is a semisolid dispersion of INSERT: A solid dosage form that is inserted into a small inorganic particles or a solution of large organ- body cavity other than the rectum. A suppository is ic molecules containing a gelling agent to provide an insert intended for application to the rectum (see stiffness. A gel may contain suspended particles. Suppository).

GRANULES (NOT PREFERRED): A dosage form composed INTRAOCULAR: A route of administration (by injection) of dry aggregates of powder particles that may con- for a sterile liquid within the eye.

tain one or more APIs, with or without other ingredi- IRRIGATION: A sterile solution or liquid intended to ents. They may be swallowed as such, dispersed in bathe or flush open wounds or body cavities.

food, or dissolved in water. Granules are frequently JELLY (NOT PREFERRED;seeGel): A semisolid dispersion compacted into tablets or filled into capsules, with of small inorganic particles or a solution of large or- or without additional ingredients. ganic molecules containing a gelling agent to pro-

GUM: A dosage form in which the base consists of a mote stiffness.

pliable material that, when chewed, releases the API LIQUID: A dosage form consisting of a pure chemical into the oral cavity. in its liquid state. This dosage form term should not

HARD-SHELL CAPSULE (NOT PREFERRED;seeCapsules): A be applied to solutions. The term is not used in article Revision In-Process type of capsule in which one or more APIs, with or names. When liquid is used as a descriptive term, it without other ingredients, are filled into a two-piece indicates a material that is pourable and conforms to its container at room temperature.

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1308 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

LOTION: An emulsion liquid dosage form applied to ORO-PHARYNGEAL: A route of administration character- the outer surface of the body. Historically, this term ized by deposition of a preparation into the buccal has also been applied to suspensions and solutions. cavity and/or pharyngeal region to exert a local or

LOZENGE: A solid dosage form intended to disinte- systemic effect.

grate or dissolve slowly in the mouth. OTIC: A route of administration (mucosal) character-

MODIFIED-RELEASE: A descriptive term for a dosage ized by deposition of a preparation into, or by way form with an API release pattern that has been deli- of, the ear. Sometimes referred to as Aural (Aural

berately changed from that observed for the imme- NOT PREFERRED).

diate-release dosage form of the same API. PASTE: A semisolid dosage form containing a high

MOLDED TABLET (NOT PREFERRED;seeTablet): A tablet percentage of finely dispersed solids with a stiff con- that has been formed by dampening the ingredients sistency. This dosage form is intended for application and pressing into a mold, then removing and drying to the skin, oral cavity, or mucous membranes.

the resulting solid mass. PELLET: A small solid dosage form of uniform, often

MOUTHWASH (NOT PREFERRED;seeSolution): Term ap- spherical, shape. Spherical pellets are sometimes re-

plied to a solution preparation used to rinse the oral ferred to as Beads (Beads NOT PREFERRED).

cavity. PILL (NOT PREFERRED but frequently incorrectly used to

NASAL: Route of administration (mucosal) character- describe a Tablet): A solid spherical pharmaceutical ized by deposition in the nasal cavity for local or sys- dosage form, usually prepared by a wet massing temic effect. technique.

OCULAR (NOT PREFERRED; see Intraocular): Route of ad- PLASTER: A semisolid dosage form supplied on a sup- ministration (by injection) indicating deposition of port material for external application. Plasters are ap- the API within the eye. plied for prolonged periods to provide protection,

OINTMENT: A semisolid dosage form, usually contain- support, or occlusion (for macerating action).

ing less than 20% water and volatiles and more than POWDER: A dosage form composed of a solid or mix- 50% hydrocarbons, waxes, or polyols as the vehicle. ture of solids reduced to a finely divided state and in- This dosage form generally is for external application tended for internal or external use.

to the skin or mucous membranes. PROLONGED-RELEASE: NOT PREFERRED;seeExtended-

OPHTHALMIC: A route of administration (mucosal) Release.

characterized by application of sterile preparation RECTAL: A route of administration (mucosal) charac- to the external parts of the eye. terized by deposition into the rectum to provide lo-

ORAL: A route of administration (gastro-intestinal) cal or systemic effect.

characterized by deposition of a preparation into RINSE: A liquid preparation used to cleanse by flush- the mouth for absorption or action in the digestive ing.

tract. SEMISOLID: Attribute of a material characterized by a

ORALLY DISINTEGRATING: A descriptive term for a solid reduced ability to flow or conform to its container oral dosage form that disintegrates rapidly in the at room temperature. A semisolid does not flow at mouth. low shear and generally exhibits plastic flow behavior. In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009] IN-PROCESS REVISION 1309

SHAMPOO: A solution or suspension dosage form used SUPPOSITORY: A solid dosage form in which one or to clean the hair and scalp. May contain an API in- more APIs are dispersed in a suitable base and mold- tended for topical application to the scalp. ed or otherwise formed into a suitable shape for in-

SOAP: The alkali salt(s) of a fatty acid or mixture of fat- sertion into the rectum to provide local or systemic ty acids used to cleanse the skin. Soaps used as dos- effect.

age forms may contain an API intended for topical SUSPENSION: A liquid dosage form that consists of sol- application to the skin. Soaps have also been used id particles dispersed throughout a liquid phase.

as and . SYRUP (NOT PREFERRED;seeSolution): A solution con-

SOFT GEL CAPSULE (NOT PREFERRED; see Capsule): A specif- taining high concentrations of sucrose or other sug- ic capsule type characterized by increased levels of ars. This term is commonly used in compounding plasticizers producing a more pliable and thicker- pharmacy.

walled material than hard gelatin capsules. Soft gel TABLET: A solid dosage form prepared from powders capsules are further distinguished because they are or granules by compaction.

single-piece sealed dosages. Frequently used for de- TAPE, MEDICATED: A dosage form or device composed livering liquid compositions. of a woven fabric or synthetic material onto which an

SOLUTION: A clear, homogeneous liquid dosage form API is placed, usually with an adhesive on one or that contains one or more chemical substances dis- both sides to facilitate topical application.

solved in a solvent or mixture of mutually miscible TINCTURE (NOT PREFERRED; see Solution): An alcoholic or solvents. hydroalcoholic solution prepared from vegetable

SPIRIT (NOT PREFERRED;seeSolution): A liquid dosage materials or from chemical substances.

form composed of an alcoholic or hydroalcoholic so- TOPICAL: A route of administration characterized by lution of volatile substances. application to the outer surface of the body.

SPRAY: Attribute that describes the generation of TROCHE (NOT PREFERRED;seeLozenge): A solid dosage droplets of a liquid or solution to facilitate applica- form intended to disintegrate or dissolve slowly in tion to the intended area. the mouth and usually prepared by compaction in

STENT, DRUG-ELUTING: A specialized form of implant a manner similar to that used for tablets. used for extended local delivery of the API to the im- mediate location of stent placement.

STRIP (NOT PREFERRED; see Tape): A dosage form or de- vice in the shape of a long, narrow, thin solid mate- rial.

SUBLINGUAL: A route of administration (mucosal) char- acterized by placement underneath the tongue and for release of the API for absorption in that region. nPoesRevision In-Process

# 2009 The United States Pharmacopeial Convention All Rights Reserved. Pharmacopeial Forum 1310 IN-PROCESS REVISION Vol. 35(5) [Sept.–Oct. 2009]

URETHRAL: A route of administration (mucosal) char- Change to read: acterized by deposition into the urethra. VAGINAL: A route of administration (mucosal) charac- INTRODUCTION terized by deposition into the . Water is widely used as a raw material, ingredient, and sol- vent in the processing, formulation, and manufacture of phar- VEHICLE: A term commonly encountered in com- maceutical products, active pharmaceutical ingredients (APIs) and intermediates, compendial articles, and analytical re- pounding pharmacy that refers to a component for agents. This general information chapter provides additional in- formation about water, its quality attributes that are not internal or external use that is used as a carrier or dil- included within a water monograph, processing techniques that can be used to improve water quality, and a description uent in which liquids, semisolids, or solids are dis- of minimum water quality standards that should be considered when selecting a water source. solved or suspended. Examples include water, This information chapter is not intended to replace existing regulations or guides that already exist to cover USA and Inter- syrups, elixirs, oleaginous liquids, solid and semisolid national (ICH or WHO) GMP issues, engineering guides, or oth- er regulatory (FDA, EPA, or WHO) guidances for water. The carriers, and proprietary products (see Excipient). contents will help users to better understand pharmaceutical water issues and some of the microbiological and chemical con- VETERINARY: Descriptive term for dosage forms intend- cerns unique to water. This chapter is not an all-inclusive writing on pharmaceutical waters. It contains points that are basic in- ed for nonhuman use.&2S (USP33) formation to be considered, when appropriate, for the proces- sing, holding, and use of water. It is the user’s responsibility to assure that pharmaceutical water and its production meet ap- plicable governmental regulations, guidances, and the com- pendial specifications for the types of water used in compendial articles. Control of the chemical purity of these waters is important and is the main purpose of the monographs in this compendi- BRIEFING um. Unlike other official articles, the bulk water monographs (Purified Water and Water for Injection) also limit how the article can be produced because of the belief that the nature and ro- h1231i Water for Pharmaceutical Purposes, USP 32 bustness of the purification process is directly related to the re- page 741. Although the majority of water used for production sulting purity. The chemical attributes listed in these is Purified Water and Water for Injection that is produced on site monographs should be considered as a set of minimum speci- (referred to as ‘‘bulk water’’), the Pharmaceutical Waters Expert fications. More stringent specifications may be needed for Committee recognizes the need for and the use of commercial- some applications to ensure suitability for particular uses. Basic ly available ‘‘packaged’’ Purified Water and Water for Injection in guidance on the appropriate applications of these waters is some production environments. In addition, there are sterile found in the monographs and is further explained in this chap- waters such as Sterile Purified Water and Sterile Water for Injection ter. (and Inhalation and Irrigation). As the tests and limits for these Control of the microbiological quality of water is important various types of waters have been updated in recent years, for many of its uses. All some of the terminology regarding ‘‘bulk’’, ‘‘sterile’’, and & ‘‘packaged’’ needs to be updated and/or clarified. The pro- Most&2S (USP33) posed remedy is to distinguish between ‘‘bulk’’ water, ‘‘sterile’’ water, and ‘‘packaged bulk’’ water in the relevant monographs and general chapters. The term ‘‘packaged waters’’ has been used as a substitute for ‘‘sterile waters’’ and as a term to de- scribe commercially available packages of Purified Water and Water for Injection. The Pharmaceutical Waters Expert Commit- tee proposes that the term ‘‘packaged waters’’ be used for the packaged form of bulk Purified Water and Water for Injection that has been produced elsewhere. Requirements for packaged waters are contained in the Purified Water and Water for Injection monographs. Sterile waters, although they are also packaged articles, have their own unique monographs and uses. The Ex- pert Committee is discouraging the use of the term ‘‘packaged water’’ to mean ‘‘sterile water’’. There are companion changes in Water Conductivity h645i and the monographs for Sterile Purified Water, Sterile Water for Injection, Sterile Water for Inhalation, and Sterile Water for Irriga- tion. All changes align the use of these terms.

(PW: A. Hernandez-Cardoso.) RTS—C76228 In-Process Revision

# 2009 The United States Pharmacopeial Convention All Rights Reserved.